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Heteroatom doping is considered an effective method to substantially improve the electrochemical performance of Ti3C2Tx MXene for supercapacitors. Herein, a facile and controllable strategy, which combines heat treatment with phosphorous (P) doping by using sodium phosphinate (NaH2PO2) as a phosphorus source, is used to modify Ti3C2Tx. The intercalated ions from NaH2PO2 act as “pillars” to expand the interlayer space of MXene, which is conducive to electrolyte ion diffusion. On the other hand, P doping tailors the surface electronic state of MXene, optimizing electronic conductivity and reducing the free energy of H+ diffusion on the MXene surface. Meanwhile, P sites with lower electronegativity owning good electron donor characteristics are easy to share electrons with H+, which is beneficial to charge storage. Moreover, the adopted heat treatment replaces –F terminations with O-containing groups, which enhances the hydrophilicity and provides sufficient active sites. The change in surface functional groups increases the content of high valence-stated Ti with a high electrochemical activity that can accommodate more electrons during discharge. Synergistic modification of interlayer structure and chemical state improves the possibility of Ti3C2Tx for accommodating more H+ ions. Consequently, the modified electrode delivers a specific capacitance of 510 F g−1 at 2 mV s−1, and a capacitance retention of 90.2% at 20 A g−1 after 10,000 cycles. The work provides a coordinated strategy for the rational design of high-capacitance Ti3C2Tx MXene electrodes.

Vegetable oils have been widely used in food, surfactants, lubricants, biodiesel, coatings, and other fields due to their advantages such as renewable, abundant, suitable for further processing, and biodegradable. On the other hand, microwave technology has attracted extensive attention in organic and polymeric chemistry because the technology can greatly shorten the reaction time, improve the yield of products, reduce side reactions, etc. This paper summarized recent advances on the microwave-assisted modification of vegetable oils or their derivatives, such as esterification of free fatty acids, transesterification of triglycerides, epoxidation, and polymerization.

The molecular targets and mechanisms of propolis ameliorating metabolic syndrome are not fully understood. Here, we report that Brazilian green propolis reduces fasting blood glucose levels in obese mice by disrupting the formation of CREB/CRTC2 transcriptional complex, a key regulator of hepatic gluconeogenesis. Using a mammalian two-hybrid system based on CREB-CRTC2, we identify artepillin C (APC) from propolis as an inhibitor of CREB-CRTC2 interaction. Without apparent toxicity, APC protects mice from high fat diet-induced obesity, decreases fasting glucose levels, enhances insulin sensitivity and reduces lipid levels in the serum and liver by suppressing CREB/CRTC2-mediated both gluconeogenic and SREBP transcriptions. To develop more potential drugs from APC, we designed and found a novel compound, A57 that exhibits higher inhibitory activity on CREB-CRTC2 association and better capability of improving insulin sensitivity in obese animals, as compared with APC. In this work, our results indicate that CREB/CRTC2 is a suitable target for developing anti-metabolic syndrome drugs., Disruption of CREB/CRTC2, a key gluconeogenic transcriptional complex, has been shown to ameliorate insulin resistance in mice. Here, the authors show that the inhibitor artipllin C and the synthetic compound A57, which presents with higher inhibitory activity, improve insulin sensitivity in obese mice by inhibiting CREB-CRTC2 interaction.

Additional file 1. Completed Standard Protocol Items: Recommendation for Interventional Trials (SPIRIT) 2013 checklist: items addressed in this clinical trial protocol.

Supplemental Material, sj-doc-1-osj-10.1177_23094990211027391 for Obesity is a risk factor for epidural lipomatosis: a meta-analysis by Bi Zhang, Haifeng Yuan, Lihong Hu and Muhammad Saad in Journal of Orthopaedic Surgery

A bio-based superhydrophobic durable cotton fabric was manufactured by using a method of ultrasonic-assisted in situ growth. The hierarchical structure of cotton fibers was generated by the deposition of the hydrophobic composite nanoparticles, which derived from the hydrolysis and co-condensation of cardanol-based benzoxazine (C-aps) and tetraethylorthosilicate (TEOS). The obtained superhydrophobic surface had a water contact angle of 158.5 ± 0.2° with special wettability. The mechanical and environmental stability of the superhydrophobic cotton fabrics were assessed through sandpaper abrasion, ultrasound treatment, high temperature tests, acid/alkaline liquids, solution immersion, and water drop experiment. Additionally, the modified cotton fabrics could separate oil-water mixtures with excellent separation efficiency (> 99.0%), high flux (as high as 6748.2 ± 237.4 L m−2 h−1), and stable reusability. The study demonstrates that the bio-based superhydrophobic cotton fabric has practical applications in the management of industrial wastewater and oil contaminants.

Novel UV-curable polyurethane acrylate (PUA) resins were developed from rubber seed oil (RSO). Firstly, hydroxylated rubber seed oil (HRSO) was prepared via an alcoholysis reaction of RSO with glycerol, and then HRSO was reacted with isophorone diisocyanate (IPDI) and hydroxyethyl acrylate (HEA) to produce the RSO-based PUA (RSO-PUA) oligomer. FT-IR and 1H NMR spectra collectively revealed that the obtained RSO-PUA was successfully synthesized, and the calculated C=C functionality of oligomer was 2.27 per fatty acid. Subsequently, a series of UV-curable resins were prepared and their ultimate properties, as well as UV-curing kinetics, were investigated. Notably, the UV-cured materials with 40% trimethylolpropane triacrylate (TMPTA) displayed a tensile strength of 11.7 MPa, an adhesion of 2 grade, a pencil hardness of 3H, a flexibility of 2 mm, and a glass transition temperature up to 109.4 °C. Finally, the optimal resin was used for digital light processing (DLP) 3D printing. The critical exposure energy of RSO-PUA (15.20 mJ/cm2) was lower than a commercial resin. In general, this work offered a simple method to prepare woody plant oil-based high-performance PUA resins that could be applied in the 3D printing industry.

Objective: Cell division cycle 7 (CDC7), a receptor serine/threonine kinase which features high-affinity with protein DBF4, plays an important role in DNA replication and DNA damage response via MCM2 phosphorylation. CDC7 has been reported to be up-regulated by about 50% in various human cancers and is being investigated as a therapeutic target in clinical trials. The purpose of this study is to investigate the in-vitro and in-vivo antitumor activities of TQB3824, a small molecule of CDC7 kinase inhibitor, in preclinical models with CDC7 overexpression. Method: Kinase inhibition activities of TQB3824 were determined with CDC7/DBF4 kinase assays. Cellular anti-proliferative activities were evaluated in COLO205 cell line and NCI-H226 cell line, which features CDC7 overexpression and no CDC7 expression, respectively. Three CDX models, colorectal cancer COLO205/SW620 and pancreatic cancer CAPAN-1 with KRAS mutation, were used to test the efficacy of TQB-3824 in vivo. Result: TQB3824 showed potent activities in both kinase inhibition and COLO205 cell anti-proliferation, with IC50 of 2.9 nM and 14.5 nM, separately. In contrast, TQB3824 showed much weaker anti-proliferative activity in NCI H226 cells with IC50 of 8154 nM. TQB3824 displayed strong antitumor efficacy in CDC7 highly expressed colorectal cancer CDX model COLO205 (TGI = 77% @5 mpk, BID), SW620 CDX model (TGI = 100% @5 mpk, BID), and pancreatic cancer CAPAN-1 CDX model (TGI = 115% @6 mpk, BID). Conclusion: We have identified a novel potent CDC7 inhibitor TQB3824, which shows high antitumor efficacy in CDC7 overexpressed solid tumor models. TQB3824 represents a promising clinical candidate for treating solid tumors with high CDC7 expression. Citation Format: Gang Li, Xiquan Zhang, Ling Yang, Xin Tian, Zhong xiong, Lihong Hu, Yuanfeng xia, Chi-chung chan, Charles Z. Ding, Shuhui Chen. Preclinical candidate TQB3824, a small molecule inhibitor of CDC7, shows strong antitumor efficacy in colorectal and pancreatic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1970.

Background: Transforming growth factor-β (TGF-β) plays a significant role in multiple physiological signaling pathways, thus occupies a pivotal position in balancing immunity and antigen tolerance. Activation of TGFβ type I receptor (TGF-βRI) recruits and phosphorylates SMAD transcription factors and promotes EMT gene expression, leading to tumor progression and invasion. Inhibition of this pathway therefore has potential to treat cancer. The preclinical evaluations of a novel TGF-βRI inhibitor ASKC852 is described. Results: ASKC852 has been shown to be a potent and highly selective inhibitor of TGF-βRI. ASKC852 inhibited SMAD phosphorylation in HEK293 cells (IC50 < 0.1 μM), a down-stream PD marker of TGF-β signaling pathway. This compound showed metabolic stability, oral bioavailability in mice and rats, with anti-tumor activity when given alone (TGI: 81.2%) in CT26 colon cancer model. In EMT6 breast carcinoma model, ASKC852 demonstrated significant synergistic effect when combined with a mouse PD-L1 antibody. Greater than 50% p-SMAD inhibition was achieved at low doses in in vivo PD studies. In addition, ASKC852 effectively inhibited tumor metastasis in 4T1-luc2 model. In a 28-days pre-clinical toxicology study, ASKC852 showed no effect on rat cardiovascular system @ 30 mg/kg. Conclusion: Our data demonstrates ASK852 is a potent and highly selective TGF-βRI inhibitor. It effectively blocked the TGF-β-SMAD signal pathway, with anti-tumor effect in syngeneic mouse models. Pharmacokinetic profile and safety properties support ASKC852 as a potential anticancer agent for the clinical treatment of solid tumors. Citation Format: Tingting Song, Min Sun, Hongyu Chen, Xiangyu Fu, Lihong Hu, Shuhua Han, Haijun Tong, Yuanfeng Xia, Jian Zuo, Shaohua Qin, Ying Chen, Charles Ding, Chichung Chan, Shuhui Chen. A novel TGF-βRI inhibitor ASKC852, possessing antitumor and PD-L1 synergistic effect activities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2291.

Objective: Homology-directed repair (HDR) pathway is the major DNA double-strand break repair pathway. BRCA-deficiency impairs this pathway, and combination with Poly(ADP-ribose) polymerase (PARP) inhibition results in cell death. This process is known as “synthetic lethality”. A proportion of breast cancer, ovarian cancer and other solid tumor patients carrying BRCA-mutated gene receive benefits from PARP inhibitors. In this study, we present in vitro activity and in vivo efficacy data of a novel small molecule PARP inhibitor, TQB3823 to support it as our clinical candidate. Method: Enzyme inhibition activities of TQB3823 were determined in PARP1/PARP2/Tankyrase 1 assays. Cellular anti-proliferative activity and selectivity were evaluated in MDA-MB-436 cell line with BRCA1 mutation and BRCA wild type MDA-MB-231 cell line. Antitumor efficacy of TQB3823 was investigated in BRCA1 mutated MDA-MB-436 breast cancer CDX model. Result: TQB3823 showed high potency and selectivity at both enzymatic and cellular level. IC50 of TQB3823 in PARP1/PARP2/Tankyrase 1 assays are 2.8/0.9/629.3 nM, respectively. It inhibited proliferation of BRCA1 mutant MDA-MB-436 cell with IC50 of 9.6 nM. In contrast, TQB3823 showed little anti-proliferative activity in BRCA-wild type MDA-MB-231 cell with IC50 >10 μM. TQB3823 demonstrated antitumor efficacy in dose dependent fashions with tumor regression was observed at 25 mg/kg in MDA-MB-436 CDX model. The level of antitumor effects was superior to niraparib at the same dose in the same study. DNA trapping experiments revealed similar potency to olaparib indicative of low toxicity. Conclusion: We have identified a novel, potent and selective PARP inhibitor TQB3823, which inhibits the proliferation of BRCA mutant cells but spares the wild type cells. In vivo study in a BRCA-deficiency tumor model confirms the high in vivo efficacy of this molecule. In conclusion, TQB3823 represents a promising differentiated clinical candidate for treating solid cancers with homology directed repair. Citation Format: Hu Yanbin, Zhang Xiquan, Yang Ling, Tian Xin, Li Gang, Hu Lihong, Charles Z. Ding, Xia Yuanfeng, Li Wei, Yin Shanshan, Chen Ying, Wu Songliang, Chen Shuhui. Characterization of TQB3823, a differentiated PARP inhibitor with anti-tumor activity in BRCA-deficiency cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2054.

Objective: Approximately 1.6-3.4% and 2-4% of NSCLC patients harbor EGFR or HER2 exon20 insertion mutations, respectively. No targeted therapy has been approved for these patients yet. NIP142 is a novel EGFR/HER2 inhibitor with potent inhibitory activities against above mentioned mutations. Purpose of this study is to provide evidence to support NIP142 as a clinical candidate for treatment of NSCLC driven by EGFR or HER2 exon20 insertion mutations. Method: Enzymatic activities of NIP142 were evaluated in EGFR/HER2 exon20 insertion mutants, including EGFR (D770_N771insNPG) and HER2 (V777_G778ins>CG). Anti-proliferative activities of NIP142 were evaluated in Ba/F3 cell lines with exon20 mutants (such as EGFR(D770_N771insSVD), EGFR(H773_V774insNPH), EGFR(V769_D770insASV), HER2(A775_G776insYVMA)), LU0387(EGFR-H773_V774insNPH), NCI-H1975 (EGFRL858R/T790M) and A431 (EGFRWT) cell lines. In vivo efficacy was evaluated in genetically engineered Ba/F3 (EGFR-D770_N771insSVD) mouse model, and LU0387 (EGFR-H773_V774insNPH) PDX model. Result: NIP142 displayed potent enzymatic inhibition activities in exon20 mutants, such as EGFR (D770_N771insNPG) (IC50 = 0.5 nM), HER2 (V777_G778ins>CG) (IC50 = 0.67 nM) and potent anti-proliferative activities in Ba/F3 cell lines with exon20 mutants, EGFR-D770_N771insSVD (IC50 = 32 nM), EGFR-H773_V774insNPH (IC50 = 32 nM), EGFR-V769_D770insASV (IC50 = 22 nM), HER2 A775_G776insYVMA (IC50 = 30 nM) respectively. NIP142 also exhibited potent anti-proliferative activities in NCI-H1975 (EGFRT790M\L858R) (IC50 = 9.4 nM), LU0387 (EGFR-H773_V774insNPH) (IC50 = 25 nM), and moderate anti-proliferation activity in EGFRWT A431cell line (IC50 = 37 nM). NIP142 was investigated in various CDX models. In particular, NIP142 significantly inhibited tumor growth in the LU0387 (EGFR-H773_V774insNPH) PDX tumor model of NSCLC, and tumor regression was achieved at 15 mg/kg. Conclusion: NIP142 is a potent EGFR/HER2 exon20 insertions inhibitor and showed excellent activities in preclinical in vitro assays and relevant tumor models. These results together with its preclinical safety data (not shown) support NIP142 to enter the clinical research to explore its potential for treating NSCLC with EGFR/HER2 exon20 insertions. Citation Format: Huijun Yin, Xu Yan, Weixue Tian, Guobiao Chu, Zhuo Wang, Xin Zhao, lu zhang, Xile Liu, Charles Z. Ding, Lihong Hu, Chengyuan Li, Gang Bai, Yuanfeng Xia, Chi-Chung Chan, Shuhui Chen. A potent and selective EGFR/HER2 exon 20 mutations inhibitor NIP142 induced tumor regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2298.

Most estrogen receptor positive (ER +) breast cancers depend on ER signaling pathway to develop. Clinical application of SERD fulvestrant effectively degraded ER, blocked its function and prolonged progression free survival of ER + breast cancer patients. However, current SERD suffers from limited bioavailability, therefore is given as intramuscular (IM) injection. In this paper, we report herein a novel indole series compounds with nanomolar range ER degradation potencies and oral systemic exposures. Selected compounds suppressed tumor growth in vivo in ER + MCF7 breast cancer CDX model via p.o. administration. All those data supported further optimizations of this analog to develop preclinical candidate as oral SERD for ER + breast cancer’s treatment.

The G1 restriction point is critical for regulating the cell cycle and is controlled by the retinoblastoma protein (Rb) pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). Selective CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib have been approved by US FDA as single agent or in combination with endocrine therapy to treat patients with HR+/Her2- breast cancer. Here, we disclose the preclinical development of CS3002 and its characterization as a novel CDK4/6 inhibitor with unique kinase inhibition spectrum. Similar to the three approved CDK4/6 inhibitors, CS3002 is highly selective for and potent against CDK 4 and 6, a feature that is expected to overcome the toxicity issues of pan-CDK inhibitors. Cell-based assays confirmed the biological activities of CS3002 by showing anti-proliferative effect, significant Rb phosphorylation inhibition, and G1 cell cycle arrest in a set of Rb-positive cancer lines. Furthermore, CS3002 showed excellent in vivo activity as a single agent, and in combinations with either endocrine therapy (fulvestrant) or PD-1 blockade (CS1003) in a set of tumor models, together with desirable ADME/PK and safety profile. CS3002 was further tested against 196 kinases in a Carna panel. In addition to CDK4 and CDK6, FLT3 and TRKA were also potently inhibited with IC50 values Citation Format: Juan Zhang, Liang Tang, Zhenhu Li, Liang Lu, Yuanwu Bao, Zhaoxiang Ren, Jingshu Ma, Yaling Huang, Zhaobing Xu, Yuanfeng Xia, Charles Z. Ding, Lihong Hu, Shuhui Chen, Archie N. Xie, Xinzhong Jon Wang. CS3002, a novel CDK4/6 inhibitor with unique kinase inhibition spectrum which may expand indications beyond breast cancer and delay acquired drug resistance [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4844.

Background: More than 30% of de novo AML patients were identified with FLT3 mutations. Two kinds of mutations, internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, account for 23% and 7% of all AML cases, respectively. FLT3 inhibitors, which have been recommended by both NCCN and ELN guidelines, are often used as single or combo agent to treat FLT3 m+ AML. However, primary and secondary acquired resistance to FLT3 inhibitors is a remarkable challenge. It has been revealed that AXL can activate FLT3, resulting in reduction of response to FLT3 inhibitors. Furthermore, TKD mutations can also lead to development of drug resistance. Therefore, FLT3/AXL dual inhibitor with potent FLT3-TKD inhibition may provide better efficacy as novel AML treatment option. Results: JRF104 is a potent FLT3/AXL dual inhibitor with a kinase inhibition IC50 value of 0.42 nM and 1.22 nM, respectively. In vitro studies suggested that JRF104 could potently inhibit the proliferation of MV4-11 and Molm-13 cells, which endogenously express FLT3-ITD mutation. JRF104 shows wide spectrum in vitro antiproliferation activity against all FLT3 mutation types, including the “gate-keeper” F691L mutation. JRF104 can effectively reduce MDA-MB-231 cell migration in vitro, accomplished by blocking tumor migration pathway regulated by AXL. In MV4-11 xenograft model, JRF104 inhibited tumor growth at the dose of 1 mg/kg, QD (TGI: 65%); significantly reduce tumor volume at 5 mg/kg, QD (TGI: 118%). In Molm-13 xenograft model, tumor volume was well controlled at 15 mg/kg, QD (TGI: 94%), and all tumor volume reduced to zero at 50 mg/kg, QD (TGI: 104%). In CT-26 syngeneic model, JRF104 enhanced anti-tumor growth effect when combined with anti-PD-1 antibody and suppressed pERK and pAKT in tumor tissues. Additionally, JRF104 demonstrated high oral bioavailability in mouse, rat, and dog. In 28 days pre-clinical toxicology studies, JRF104 was well tolerated in all tested rats. HNSTD and NOEAL were determined to be 20 mg/kg QD and 3 mg/kg QD, respectively. All results support that JRF104 with high efficacy and safety. Conclusion: JRF104 demonstrated consistently potent inhibition of FLT3 and strong antitumor efficacy against FLT3-driven tumors in preclinical studies. Based on these datas, JRF104 may overcome resistance caused by AXL and FLT3-TKD mutation, representing a novel promising clinical antitumor agent for treating AML patients with FLT3 mutations. Citation Format: yuquan wei, Xiawei Wei, Yanzhong Zhang, Wanru Qin, Xiangyu Fu, Lihong Hu, Yuanfeng Xia, Jian Zuo, Zhong Xiong, Shanshan Yin, Shaohua Qin, Ge Dong, Ying Chen, Charles Ding, Chichung Chan, Shuhui Chen. Development of new FLT3/AXL dual inhibitor JRF104 with potent FLT3-TKD inhibition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3766.

e16126 Background: GST-HG161 is an orally bioavailable novel potent and highly selective c-Met inhibitor, which displayed significant antitumor activity in preclinical models as well as very desirable pharmaceutical properties for oral dosing. Preclinical studies demonstrated that GST-HG161 has the potential to be effective in HCC patients with active c-Met signaling. Methods: This is an open label, first-in-human, single center, dose-escalation study (NCT04228406) utilizing an accelerated dose escalation design using single patient cohorts for the first two dose levels (60 and 150 mg) followed by a conventional 3+3 design at the 3rd dose cohort (300 mg). Dose escalation is expected to continue to the proposed 7th dose cohort (900 mg). The objective of the study is to determine the maximum tolerated dose and/or recommended Phase II dose, dose limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics and preliminary signals of anticancer efficacy of GST-HG161 in patients with advanced solid tumors. Eligible patients are adults with advanced solid tumors refractory to standard therapies with confirmed c-Met positive. The definition of c-Met positive is a) IHC expression of c-Met (positive criteria: 1+ and above) and/or b) FISH amplification of c-Met and/or c) MET exon 14 (METex14) skipping. GST-HG161 is administered orally once-a-day starting on day 1 of each 21 days cycle. Results: To date, 6 patients (CRC 2, Gastric 1, NSCLC 1, HCC 1, Cholangiocarcinoma 1) were enrolled to 3 dose levels (60, 150, and 300 mg). Of these 6 patients, 4 had discontinued GST-HG161 treatment at the data cut-off date of Feb 1, 2020, due to progressive disease (3) and adverse event (1). Two patients at the 300 mg cohort are still on treatment. Overall, 4/6 patients showed no drug-related AEs > Grade 1. One patient reported a DLT: asymptomatic Grade 3 lipase elevation after a single dose of 60mg. To date, no other patients showed elevations of lipase and amylase. Bioanalysis of PK samples from study patients are currently ongoing. PK summary will be reported in the presentation. Conclusions: GST-HG161 has been well tolerated to date in study patients with a manageable safety profile. The dose escalation is expected to continue to the proposed 7th cohort at 900 mg. Clinical trial information: NCT04228406 .

Enzymatic hydrolysis lignin (EHL) derived from bio-ethanol production is attracting increased attention for use as a substitute for petroleum-based phenol in phenolic resins. In this work, EHL was successfully liquefied into small phenolic compounds catalyzed by oxalic acid in the presence of phenol. Experiments were designed to determine the effects of different replacement percentages of phenol by EHL on the residue content (RC) and the combined phenol (CP). Up to a 55% weight of phenol was substituted by liquefied EHL to formulate a novolac bio-based phenolic resin (EHL–PF). The differences between EHL and liquefied EHL, PF and EHL–PF were studied by Fourier transform infrared (FT-IR) spectroscopy, gel permeation chromatography (GPC), 1H NMR spectroscopy, scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). RC was found to increase with the increasing replacement percentage, while CP was found to increase at a lower replacement percentage and decrease at a higher replacement percentage. EHL–PF possessed comparable properties to those of commercial products.

Background: The transforming growth factor-β (TGF-β) signaling pathway has been shown to play an important role in various cellular processes including growth inhibition, cell migration, tumor invasion, epithelial-mesenchymal transition, and immune-suppression. TGF-βs are often overexpressed in various types of cancers, and the anti-TGF-β therapy has been pursued intensively for cancer treatment. Results: GFH018 is a potent, selective inhibitor of TGF-βRI with a kinase inhibition activity IC50 of 70.5 nM. Our studies demonstrated that GFH018 could inhibit TGF-β-induced SMAD phosphorylation and migration of tumor cells. GFH018 is a potent immune regulator in that it could inhibit in vitro Treg cell induction and reverse M2 phenotype to M1, leading to increased pro-inflammatory cytokine production. In addition, GFH018 exhibited a significant inhibitory effect on in vitro angiogenesis formation assay. Importantly, GFH018 has shown promising anti-tumor efficacy in multiple in vivo mouse syngeneic models as a monotherapy as well as in combination with an anti-PD-(L)1 antibody. Following oral administration, GFH018 demonstrated fast absorption, and high oral bioavailability in preclinical animal species including mouse, rat, and dog. Results from the toxicology studies in rat and dog have also supported further development of GFH018. Conclusion: GFH018 has the potential to be developed as a monotherapy or combinational therapy with checkpoint inhibitors for advanced solid tumor patients. The first-in-human clinical trial is scheduled in 2019. Citation Format: Gang Hu, Rong Zhao, Fusheng Zhou, Jiong Lan, Biao Zheng, Qiang LU, Jianyu Lu, Lifang Wu, Fei Sun, Lihong Hu, Shuhua Han, Haijun Tong, Yuanfeng Xia, Wei Li, Liping Ma, Ying Chen, Charles Ding, Chichung Chan, Shuhui Chen. GFH018, a novel TGF-βRI inhibitor, for the treatment of advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3072.

Objectives: Evasion of apoptosis and avoidance of immune surveillance represent two key hallmarks of cancer. Members of the inhibitor of apoptosis (IAP) gene play important interconnecting roles in both of these characteristic pathways of tumorigenesis, providing a critical nexus in targeting of cancer. Small-molecule antagonists of the IAPs, known as Smac mimetic compounds (SMCs), are in quick clinical development for cancer therapy. We disclose here a novel IAP antagonist TQB3728 and its preclinical evaluation on tumor therapy. Methods: The biochemical activities of TQB3728 for cIAP1 BIR3, cIAP2 BIR3 and XIAP BIR3 were measured by the corresponding biochemical assays. The in vitro anti-proliferative activity was evaluated on MDA-MB-231 and EMT6 cell lines. The in vivo antitumor activity of TQB3728 was evaluated in two cell-derived xenograft (CDX) models of TNBC (MDA-MB-231) and lymphoma (Karpas 422), and one syngeneic model of TNBC (EMT6). PK/PD was assessed by western blot analysis of cIAP1 expression and cleaved caspase 3 level in the treated tumor tissues. Results: TQB3728 displayed potent biochemical activities for cIAP1 BIR3, cIAP2 BIR3 and XIAP BIR3 with IC50 of 0.7, 11.8 and 22.5 nM, respectively. The expected anti-proliferative activities were also observed in both tumor cell lines, with a IC50 of 14.3 Nm for MDA-MB-231, and IC50 of 149.5 nM for EMT6 in the presence of exogenous TNFα (1 ng/ml). TQB3728 showed in vivo antitumor activity in the MDA-MB-231 CDX model with 89.8% TGI @30 mpk QD, which is better than LCL-161 (71.9% TGI @30 mpk, QD). TQB3728 also showed good antitumor activity in vivo in the Karpas 422 lymphoma CDX model with 112.2% TGI @100 mpk Q3D. In EMT6 tumor-bearing mice, the combination of TQB3728 and anti-PD1 antibody significantly regressed the tumor growth (TGI = 106.3%), whereas monotherapies only displayed moderate activities ( 60.6% and 0.4% TGI for anti-PD1 and TQB3728, respectively). Western blot analysis of the tumor samples showed that TQB3728 promoted caspase 3 cleavage, indicating that the tumor growth inhibition could be mediated by cell apoptosis signaling. Conclusions: We have discovered a potent orally active IAP antagonist, TQB3728, which shows activity of cIAP1 inhibition and strong antitumor activity in both in vitro and in vivo preclinical tumor models. These results are highly promising and warrant moving the compound forward to clinical investigation. Citation Format: Yingchun Liu, Xiquan Zhang, Ling Yang, Xin Tian, Tiantian Dong, Charles Z. Ding, Lihong Hu, Zhaobing Xu, Yuanfeng Xia, Haijuan Tong, Wenxi Li, Lijuan Hou, Chichung Chan, Shuhui Chen. Preclinical evaluation of TQB3728, a potent orally active IAP antagonist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 724.

Objective: Non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor-activating mutations (EGFRm+) have a much higher risk of developing CNS metastases. The cumulative incidence of BM and LM in these patients is more than 50%. These patients have poor prognosis as there are no approved drugs for these indications. Currently approved drugs can neither effectively treat brain metastases nor prevent development of the brain metastases due to their limited blood-brain-barrier (BBB) penetration. TUL-001 is a potent oral EGFR inhibitor, which has excellent potency and BBB (blood brain barrier) penetration ability, it can potently induces tumor regression both in the brain metastases and subcutaneous animal models. Methods: The anti-proliferative activity of TUL-001 was evaluated in PC-9 (EGFRExon19 Del), and A431 (EGFRWT) NSCLC cell lines. The anti-tumor activity was evaluated in PC-9-luc Lung cancer brain metastases model, which was monitored by an IVIS Xenogen imaging system. The in vivo anti-tumor activity also evaluated in PC-9 subcutaneous transplantation tumor model. Effects on EGFR signaling pathway were assessed by western blot analysis of the downstream effector proteins p-EGFR (Y1068), p-AKT (Ser473) and p-ERK (Thr202/Tyr204). Results: TUL-001 displayed potent anti-proliferative activity in the EGFR mutant cell line PC-9 (IC50 =3.74 nM), and less potent activity in the A431 (EGFRWT) cell line (IC50 = 54.1 nM), it has about 14 fold selectivity for EGFRExon19 Del over EGFRWT. TUL-001 significantly inhibited tumor growth at all doses tested in the PC-9-luc brain metastases model, and significantly prolong the overall survival for the test animals. In the PC-9 subcutaneous transplantation tumor model, TUL-001 can also shrinkage the tumors, and the TGI for the lower dose group (2.5mpk) was more than 120%. Western blot analysis of the tumor samples in the brain metastases model study showed that TUL-001 inhibited p-EGFR (Y1068), p-AKT (Ser473), and p-ERK (Thr202/Tyr204), indicating that the tumor growth inhibition was through inhibition of the resistant mutant EGFR. Conclusion: TUL-001 is a potent brain penetrant EGFR inhibitor, and showed excellent antitumor activity in preclinical tumor models. These results warrant TUL-001 going to the clinic study for exploration of its potential for treating EGFRm+ NSCLC cancer with and without brain metastasis. Citation Format: Xile Liu, Liwei Mu, Bin Liu, Shouting Wu, Degang Wang, Lu Zhang, Charles Z Ding, Lihong Hu, Weifeng Mao, Zhenzhen Zhu, Chen Chen, Yuanfeng Xia, Chichung Chan, Shuhui Chen. Preclinical evaluation of TUL-001, an EGFR inhibitor for the treatment of NSCLC with brain metastasis (BM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1316.

Objective: Osimertinib is the 3rd generation EGFR inhibitor, which has been approved for the treatment of NSCLC patients with EGFRT790M. More recently, a tertiary EGFRC797S mutation was reported as the dominant resistance (40~20%) mechanism to Osimertinib. The emergence of C797S mutation prevent covalent bond formation with Osimertinib, and caused the drug resistance. So, it’s an urgent demand for new EGFR inhibitors that can effectively inhibit EGFR triple mutant, d746-750/T790M/C797S & L858R/T790M/C797S. Here, we disclose our clinical candidate, TQB3804, as a novel 4th generation inhibitor that potently inhibits triple mutants. Methods: The enzyme activities of TQB3804 for EGFRd746-750/T790M/C797S, EGFRL858R/T790M/C797S, EGFRd746-750/T790M, EGFRL858R/T790M, and EGFRWT were measured with corresponding kinase assays. The anti-proliferative activity was evaluated in Ba/F3 (EGFRd746-750/T790M/C797S), NCI-H1975 (EGFRd746-750/T790M/C797S), PC9 (EGFRd746-750), and A431 (EGFRWT) cell lines, and the phosphorylation of EGFR was also evaluated in Ba/F3 (EGFRd746-750/T790M/C797S) cell line. Antitumor activity of TQB3804 was evaluated in three triple mutant cell-derived tumor xenograft (CDX) models Ba/F3 (EGFRd746-750/T790M/C797S), NCI-H1975 (EGFRd746-750/T790M/C797S), and PC9 (EGFRd746-750/T790M/C797S) and one Osimertinib resistant patient-derived xenograft (PDX) model of NSCLC (LUPF104, EGFRd746-750/T790M/C797S). Results: TQB3804 displayed potent enzymatic activities for EGFRd746-750/T790M/C797S, EGFRL858R/T790M/C797S, EGFRd746-750/T790M, and EGFRL858R/T790M with IC50 of 0.46, 0.13, 0.26, and 0.19 nM respectively, and has similar enzymatic activity for EGFRWT (IC50 = 1.07) to Osimertinib. It also showed expected anti-proliferative activity in 4 cell lines, Ba/F3 (EGFRd746-750/T790M/C797S), NCI-H1975 (EGFRd746-750/T790M/C797S), PC9 (EGFRd746-750), and A431 (EGFRWT), with IC50 of 26.8, 163, 45, and 147 nM, respectively. The phosphorylation for EGFR in Ba/F3 (EGFRd746-750/T790M/C797S) cell line was potently inhibited with IC50 =18.5 nM. TQB3804 significantly inhibited tumor growth in the triple mutant Ba/F3 (EGFRd746-750/T790M/C797S), NCI-H1975 (EGFRd746-750/T790M/C797S), and PC9 (EGFRd746-750/T790M/C797S) CDX models, as well as in the LUPF104 PDX model. Western blot analysis of the tumor samples in the Ba/F3 (EGFRd746-750/T790M/C797S) CDX model showed that TQB3804 inhibited p-EGFR, p-AKT and p-ERK indicating that the tumor growth inhibition was through inhibition of the resistant triple mutant EGFR. Conclusions: We have identified a potent orally active 4th generation EGFR inhibitor, TQB3804. It can inhibit the activity of Osimertinib resistant triple mutant EGFR, and showed strong antitumor activity in corresponding in vitro and in vivo preclinical assays. These results are considered highly promising and warrant moving the compound forward to clinical investigation. Citation Format: Xile Liu, Xiquan Zhang, Ling Yang, Xin Tian, Tiantian Dong, Charles Z Ding, Lihong Hu, Lingyu Wu, Lele Zhao, Jun Mao, Qusheng Ji, Shaoyu Yan, Zhenzhen Zhu, Yuanfeng Xia, Chichung Chan, Shuhui Chen. Preclinical evaluation of TQB3804, a potent EGFR C797S inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1320.

Additional file 13: Table S12. The NCI, descriptors and errors based on PBE-D3/6-31G* calculations.

Additional file 1: Table S1. The full list of the molecular descriptors.

Additional file 9: Table S8. The NCI, descriptors and errors based on WB97XD/6-31G* (Îľ=4.20) calculations.

Additional file 8: Table S7. The NCI, descriptors and errors based on WB97XD6-31G* calculations.

Additional file 7: Table S6. The NCI descriptors and errors based on WB97XD/6-31G*(vac) calculations.

Additional file 3: Table S2. The NCI, descriptors and errors based on M062X/6-31G*(vac).

Additional file 6: Table S5. The NCI, descriptors and errors based on M062X/6-31+G* calculations.

Additional file 2. The Matlab code for GRNN corredction models.

Additional file 10: Table S9. The NCI, descriptors and errors based on B3LYP/6-31G* calculations.

Additional file 5: Table S4. The NCI, descriptors and errors based on M062X/6-31G*(Îľ=4.20) calculations.

Additional file 4: Table S3. The NCI, descriptors and errors based on M062X/6-31G* calculations.

Additional file 11: Table S10. The NCI, descriptors and errors based on B3LYP-D3/6-31G* calculations.

Objective: Endocrine therapy (ET) now is the standard of care (SOC) for ER+ breast cancer treatment. The representative drug of ET is tamoxifen, a selective estrogen receptor modulator (SERM) that inhibits ER+ breast cancer growth by antagonizing ER function. Tamoxifen displays promising efficacy but also brings problems such as increased endometrial cancer risk and acquired resistance. SERD fulvestrant controls ER+ breast cancer by degrading in-cell ER. It shows improved efficacy in advanced or tamoxifen-resistant (TamR) breast cancer patients and is recently approved as first-line treatment for ER+ breast cancer. However, due to its poor PK profile, this drug could only be administrated intramuscularly, which restricts its applicable patient population. Thus, developing an oral SERD is still an unmet medical need. Method & Results: We have discovered an oral SERD, LX-039. LX-039 is a novel indole series compound. It robustly degraded ER in MCF-7 breast cancer cells (IC50 = 1.53 nM) and inhibited MCF-7 cell proliferation (IC50 = 2.56 nM). Besides, LX-039 exhibited good PK profile across species, F for mice, rat and dog were 32.2%, 44.5% and 48.1% respectively. Dose to p.o. AUC showed linear relationship, and very high p.o. AUCs could be obtained at high doses. For rat @500 mpk, p.o. AUC reached to 4.52M nM.h, and dog @300 mpk, p.o. AUC reached to 1.5M nM.h. LX-039 displayed promising in vivo antitumor efficacy. In naive MCF-7 breast cancer model, TGI was 87% @ 20 mpk; in TamR MCF-7 model, TGI was 70% @100 mpk. What makes LX-039 more advantageous is its safety profile. LX-039 showed purer ER antagonism. In rat uterine growth inhibition assay, the inhibition rate reached to 94% while inhibition rate of GDC-0810 and AZD-9496 were 65% and 89%, respectively. It had a clean CYP inhibition profile by various CYP assays, which indicates a low DDI risk. LX-039 selectively antagonizes ER without affecting other nuclear receptors such as AR, GR and PR. It showed a clean inhibition profile for a selected kinase/GPCR panel (IC50 >3 μM) and was negative in the GABA gated ion channel assay (IC50 > 10 μM) and the mini Ames test. In the 14 day rat non-GLP tox study, NOAEL of LX-039 was determined to be 300 mpk. Conclusion: The antitumor efficacy of LX-039 as demonstrated in the preclinical tumor models is highly encouraging and warrants testing the compound in the clinic as an oral SERD for treating ER+ breast cancer. The IND enabling studies of LX-039 are ongoing, and IND filing scheduled in the mid of 2018. Citation Format: Jianyu Lu, Lihong Hu, Ping Wang, Yusong Zhu, Peng Zou, Dongdong Wu, Charles Z. Ding, Shuhui Chen. Novel indole compound LX-039 as an oral selective estrogen receptor degrader (SERD) for treating estrogen receptor positive (ER+) breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1804.

Objective: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Studies indicate that aberrant activation of mesenchymal-epithelial transition factor (c-MET) is associated with HCC development. Blocking c-MET signaling shows antitumor efficacy in patients with HCC. Thus, c-MET has been an attractive therapeutic target for HCC. We disclose here for the first time a potent and selective c-MET inhibitor GST-HG161 and show the antitumor efficacy data in preclinical models of HCC. Method: MHCC97H HCC cell line with c-MET overexpression was used to evaluate the anti-proliferative activity of GST-HG161 in a 120-hour viability assay. Selectivity was evaluated with a panel of cell lines without overexpression of c-MET. Daily oral administration of GST-HG161 doses of 1, 3, 10 and 30mg/kg was used to evaluate its in vivo antitumor efficacy in two animal models of HCC with c-MET overexpression, MHCC97H xenograft (CDX) model and LI-03-0317 xenograft (PDX) model. The c-MET protein levels and gene copy number in LI-03-0317 PDX were assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. High c-MET expression in LI-03-0317 PDX was determined by the presence of tumor cells with membrane staining of 3+ intensity. Effect of GST-HG161 on c-MET signaling inhibition was assessed by western blot analysis of downstream effector proteins including p-MET, p-AKT and p-ERK. Result: GST-HG161 displayed potent anti-proliferative activity in MHCC97H HCC cell line (IC50 = 5 nM) while showed little activity in the cell lines without c-MET overexpression. It significantly inhibited tumor growth at tested doses (3, 10 and 30mg/kg) (P Conclusion: GST-HG161 is a potent and highly selective c-MET inhibitor. Its excellent antitumor efficacy as shown in the HCC mouse models provide us with confidence that GST-HG161 has high potential in the clinic for treating patients of HCC with high c-MET activity. Citation Format: Xiongbin Xu, Gang Li, Lihong Hu, Junguo Hao, Charles Z. Ding, Shuhui Chen. Preclinical evaluation of GST-HG161, a potent and highly selective c-MET inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4792.

Objective: Heat Shock Protein 90 (Hsp90) is a molecular chaperone that mediates the post-translational stability of its protein substrates, many of which are onco-proteins. Hsp90 is emerging as an important target for cancer therapy because its inactivation may abrogate multiple signaling pathways simultaneously, irrespective of the mutational status of proteins involved. We disclose here our clinical candidate WXFL1024H251, a novel second-generation small-molecule Hsp90 inhibitor with a chemical structure unrelated to the first generation, the ansamycin family of Hsp90 inhibitors. Method: The anti-proliferative activity of WXFL1024H251 was evaluated in a variety of cancer cell lines in a 96-hour viability assay. QW, Q2W or TIW intravenous administration of at doses of 5~50 mg/kg was used to evaluate the in vivo anti-tumor activity of WXFL1024H251 in BT474 cell line-derived xenograft (CDX) breast cancer model. Effects of WXFL1024H251 on HSP90 function were assessed by western blot analysis of PD markers HSP70, Her2 and p-Her2 in the BT474 tumors. Result: A panel of 20 cancer cell lines were screened for sensitivity to WXFL1024H251. Proliferation of 2 cancer cell lines A549 and BT474 were potently inhibited by WXFL1024H251, with IC50 of 0.007 μM and 0.009 μM, respectively. A549 cell line has KRAS mutation and medium to high EGFR expression. BT474 is an ER+ and ERBB2+ breast cancer cell line. In the BT474 tumor model, 3 week treatment with WXFL1024H251 showed good antitumor efficacy with T/C values of 36% at 7.5 mg/kg Q2W and 45% at 10 mg/kg QW; toxicity were acceptable with both dosing regiments. Conclusion: These preclinical studies showed good antitumor efficacy of WXFL1024H251, which was associated with client protein maturation and HSP70 up-regulation in the tumor tissue. WXFL1024H251 may represent a novel promising clinical antitumor agent for treating breast cancer and other cancer types with high expression of HSP90. Citation Format: Xiaobing yan, Charles Z. Ding, Lihong Hu, Wei Huang, Shuhui Chen, Dongdong Wu, Jiahu Wu, Guoqiang Ma, Qiyao Zhang, Rui Gao, Yusong Zhu, Tiantian Dong, Yizhong Zhu, Caixia Yan, Yan Yan. Preclinical evaluation of WXFL1024H251, a potent second-generation HSP90 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1672.

Objective: Patients of non-small cell lung cancer (NSCLC) with activating EGFR mutations initially respond to the first generation reversible EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib. However, most of the patients acquire resistance within 10~16 months. The most common mechanism of resistance is the EGFR T790M mutation. In addition, selectivity of the EGFR inhibitors is important, as inhibition of EGFR wild type can lead to dose limiting toxicities, including rash and diarrhea. This may be the reason why the second generation irreversible EGFR inhibitors, such as afatinib, which also inhibit EGFRWT, is not widely used. Here, we disclose our clinical candidate compound E-191 as a novel irreversible inhibitor that potently inhibits the resistance mutant forms of EGFR with a good selectivity sparing EGFRWT. Method: The anti-proliferative activity of E-191 was evaluated in NCI-H1975 (EGFRT790M/L58R), HCC827 (EGFRd746-750), and A431 (EGFRWT) cell lines. Daily oral administration of E-191 at 3 doses was used to evaluate the in vivo anti-tumor activity in three cell-derived tumor xenograft (CDX) models, NCI-H1975, HCC827, and Ba/F3 (EGFRT790M /d746-750). The in vivo selectivity was evaluated in the A431 (EGFRWT) CDX model. Effects on EGFR signaling pathway were assessed by western blot analysis of the downstream effector proteins p-EGFR (Y1068), p-AKT (Ser473) and p-ERK (Thr202/Tyr204). Result: E-191 displayed potent anti-proliferative activity in the EGFR mutant cell lines NCI-H1975 (IC50 = 22 nM) and HCC827 (IC50=1.9 nM), and a much less potent activity in the EGFRWT A431 cell line (IC50 = 531 nM). E-191 has about 24 fold selectivity for EGFRT790M over EGFRWT. E-191 potently inhibited tumor growth at all doses tested (P Conclusion: We have demonstrated with in vitro and in vivo preclinical models that E-191 is a selective inhibitor of the resistance mutant forms of EGFR, potently inhibiting EGFRT790M but not EGFRWT. These results make us believe that E-191 has a good potential in the clinic for the treatment of resistant EGFR driven NSCLC. Citation Format: Liu Xile, Lihong Hu, Charles Z Ding, Weifeng Mao, Liqing Wang, Xiaohe Shi, Chaofeng Long, Xiaoxin Chen, Haijun Li, Xing Liu, Zhuowei Liu. Preclinical evaluation of E-191, a highly selective EGFR T790M inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4788.

Objective: The G1 restriction point is critical for regulating the cell cycle and is controlled by the retinoblastoma protein (Rb) pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). Selective CDK4/6 inhibitors, such as palbociclib and ribociclib have been approved by US FDA in combination with letrozole to treat patients with HR+/Her2- breast cancer, and selective CDK4/6 inhibitor LY2835219 is in Phase 3 trials for the same and related indications. Here, we disclose TQB3616 for the first time, a novel selective, potent, oral inhibitor of CDK4/6. Method: The anti-proliferative activity of TQB3616 was evaluated in a panel of 18 Rb-proficient cell lines in a 72-hour viability assay. Daily oral administration was used to evaluate in vivo antitumor activity of TQB3616 in the MCF-7 cell-derived xenograft (CDX) breast cancer model. Effect on CDK4/6-cyclin D1-Rb signaling was assessed by western blot analysis of downstream effector protein p-Rb. In vivo antitumor activity of TQB3616 was also tested in a patient-derived xenograft (PDX) lung cancer model LU-01-0393. Result: TQB3616 displayed potent anti-proliferative activity in 8 of 18 Rb-proficient cancer cell lines (>50% inhibition at 0.3 µM). Inhibition of p-Rb in the tumor samples was verified by western blot analysis. TQB3616 showed in vivo antitumor activity in the MCF-7 CDX model with TGI of 60% @7.5 mpk and 93% @15 mpk, better than palbociclib (TGI = 52% @20 mpk, 80% @40 mpk) and LY2835219 (TGI = 45% @7.5 mpk, 76% @15 mpk). TQB3616 also showed good in vivo antitumor activity in the LU-01-0393 lung cancer PDX model with 65% of TGI @35 mpk. Conclusion: TQB3616 is a potent and selective CDK4/6 inhibitor and shows excellent antitumor activity in preclinical tumor models. These results warrant TQB3616 going to the clinic for exploration of its potential for treating HR+/Her2-/Rb+ breast cancer as well as other Rb+ cancer types. Citation Format: Xu Zhaobing, Hu Lihong, Liu Yingchun, Charles Z. Ding, Xiaoyu Zhu, Chen Chen, Yusong Zhu, Jiahu Wu, Dongdong Wu, Shuhui Chen, Xiquan Zhang, Ling Yang, Xin Tian. Preclinical evaluation of TQB3616, a highly potent and selective small-molecule CDK4/6 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5778.

Objective: AKT is a component of the PI3K/AKT/mTOR (PAM) pathway, which plays an important part in cell proliferation, growth and survival, activated in many cancers and has been validated as a therapeutic target in the clinic. Inhibition of AKT activity can block the PAM pathway and proliferation of various types of tumor cells with loss of tumor suppressor PTEN, mutational activation of p110a catalytic subunit of PI3K and amplification of the gene encoding either AKT or PI3K. The purpose of this study is to investigate the in vitro and in vivo antitumor activity of HZB0071, a small molecule AKT kinase inhibitor, in preclinical models of solid cancer with AKT overexpression. Method: Kinase inhibiting activity of HZB0071 was determined with AKT1, 2, 3 kinase assays. Cellular anti-proliferative activity was evaluated with AKT overexpressed LNcap cell line and DU145 cell line without AKT overexpression. The antitumor activity of HZB0071 was evaluate in vivo and the synergistic effect combined with Paclitaxel in AKT highly expressed patient-derived mouse xenograft (PDX) models of Gastric Cancer ST-02-0013 and cell-derived mouse xenograft (CDX) models of Breast Cancer BT474. Result: HZB0071 displayed potent kinase inhibiting activity for AKT1, 2, 3 with IC50 1.3±0.41 nM, 50.3±13.4 nM and 90.4±5.84 nM, respectively. HZB0071 inhibited cell proliferation in AKT overexpressed LNcap cells with IC50 67±7 nM. In contrast, HZB0071 showed much weaker anti-proliferative activity in DU145 cells with IC50 >10,000 nM. HZB0071 showed antitumor efficacy in AKT highly expressed gastric cancer PDX model ST-02-0013 (TGI = 62% @30 mpk, QD as single agent; TGI = 61% @15 mpk + Paclitaxel @10 mpk, QD, in combination with Paclitaxel), as well as in the breast cancer BT474 CDX model (TGI = 88% @30 mpk + Paclitaxel @15 mpk, QD). Conclusion: We have identified a novel potent AKT inhibitor HZB0071. Preclinical studies shows antitumor efficacy of HZB0071 in AKT overexpressed solid cancer models. HZB0071 represents a promising clinical candidate for treating solid cancers with high AKT expression. Citation Format: Gang Li, Lihong Hu, Weifeng Mao, Dongfang Li, Charles Z. Ding, Shuhui Chen. Preclinical evaluation of HZB0071, a small molecule inhibitor of AKT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5788.

The Encryption algorithm of Hill is Password system of many forms and was put forward by Hill in 1929. Basic thought of Hill encryption algorithm is to change L pieces of plaintext characters into L pieces of ciphertext characters through linear translation; Decryption only does inverse transformation. Hill password can finely resist frequency analysis and using ciphertext attack is very much difficult to break through, But it is easy to be broken through by use of plaintext. Characterizing this weakness, The article proposes an improved algorithm named P-Hill algorithm based on the encryption algorithm of Hill.The algorithm inherits resist frequency analysis and the characteristic with high efficiency; Strengthening the intensity of encryptioning, at the same time. The analysis indicates that the structure of P-Hill algorithm is compact, arrangement is proper and there is better execution efficiency.

Despite of their success, the results of first-principles quantum mechanical calculations contain inherent numerical errors caused by various approximations. We propose here a neural-network algorithm to greatly reduce these inherent errors. As a demonstration, this combined quantum mechanical calculation and neural-network correction approach is applied to the evaluation of standard heat of formation $\DelH$ and standard Gibbs energy of formation $\DelG$ for 180 organic molecules at 298 K. A dramatic reduction of numerical errors is clearly shown with systematic deviations being eliminated. For examples, the root--mean--square deviation of the calculated $\DelH$ ($\DelG$) for the 180 molecules is reduced from 21.4 (22.3) kcal$\cdotp$mol$^{-1}$ to 3.1 (3.3) kcal$\cdotp$mol$^{-1}$ for B3LYP/6-311+G({\it d,p}) and from 12.0 (12.9) kcal$\cdotp$mol$^{-1}$ to 3.3 (3.4) kcal$\cdotp$mol$^{-1}$ for B3LYP/6-311+G(3{\it df},2{\it p}) before and after the neural-network correction., Comment: 5 pages, 3 figures, REVTeX4 style, submitted to Phys.Rev.Letters