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Introduction: FGFRs play important roles in cancer development and inhibition of FGFR could disrupt tumor cell proliferation and growth. Four selective FGFR inhibitors have been approved (erdafitinib, pemigatinib, infigratinib, and futibatinib) and several others are in clinical development. Unfortunately upon treatment with these first-generation FGFR inhibitors, acquired resistance often develops and is frequently associated with the emergence of secondary FGFR2/3 kinase domain mutations. Therefore, selectively targeting FGFR2/3 as well as their resistant mutations may render a second-generation treatment approach for the refractory/relapsed patients. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a novel, next-generation, and highly selective FGFR inhibitor, ABSK121. This novel inhibitor demonstrated robust anti-tumor activity in FGFR-dependent tumor models with strong activities against not only de novo but also acquired resistant mutations. Method: ABSK121 was evaluated in biochemical and cellular proliferation experiments for its inhibition on wile type FGFR enzymatic activity and FGFR-dependent cancer cell proliferation. Its potency against FGFR mutations was also analyzed in relevant biochemical and cellular experiments. Efficacy studies were conducted in multiple tumor models to confirm its in vivo activities. Preliminary selectivity profile and ADME profiles were also evaluated. Results: ABSK121 inhibited wild type FGFRs with IC50 Conclusion: ABSK121, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR inhibitor with great potency against resistant FGFR mutations. Its superior profile supports fast-track preclinical and clinical development. Citation Format: Haiyan Ying, Wenqun Xin, Haibing Deng, Yuan Zhao, Hongping Yu, Zhui Chen, Yao-chang Xu. Discovery and characterization of a next-generation FGFR inhibitor overcoming FGFR resistant mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB317.

Introduction: Aberrant activation of FGF19-FGFR4 signaling pathway plays an essential role in the tumorigenesis of Hepatocellular carcinoma (HCC) and FGFR4 inhibitors have shown preliminary efficacy in recent clinical trials for patients with FGF19 overexpression. However, the observed responses only lasted a few months before tumors relapse. Acquired FGFR4 resistant mutations were found in ~30% of FGFR4 inhibitor responsive patients. Similar FGFR4 mutations haven also been found de novo in about 7-10% of Rhabdomyosarcoma (RMS) and ER-treated invasive lobular carcinoma patients. First generation FGFR4 inhibitors have minimal activity against these de novo or acquired resistant mutations. Therefore, next-generation of FGFR4 inhibitors are needed to overcome these resistant FGFR4 mutations to provide better treatment options for patients. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a next-generation small molecule FGFR4 inhibitor, ABSK012, and demonstrated its strong activities against de novo and acquired resistant FGFR4 mutations while retaining inhibition for wild-type FGFR4. Method: Inhibitory activity of ABSK012 against FGFR4 and FGFR4 mutants was evaluated by MSA assay and its inhibition on FGFR4-dependent cell proliferation was evaluated by Celltiter-Glo assay in wile type FGFR4-dependent cancer cell lines or mutant FGFR4-dependent Ba/f3 cell lines. Its selectivity against other FGFR family member and kinases was analyzed by cellular and KinomeScan profiling. Efficacy studies were conducted in HCC xenograft models and mutant FGFR4-dependent xenograft models including a RMS PDX model harboring FGFR4 V550L mutation. Results: ABSK012 demonstrated strong potency over multiple FGFR4 mutants that are insensitive to a first generation FGFR4 inhibitor BLU-554. It also inhibited wild-type FGFR4 with IC50 Conclusion: ABSK012, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR4 inhibitor overcoming FGFR4 mutations resistant to first-generation inhibitors. Its superior preclinical profile supports its fast-track development into clinic. Citation Format: Haiyan Ying, Nannan Zhang, Haibing Deng, Fei Yang, Wenqun Xin, Bin Shen, Hongping Yu, Zhui Chen, Yao-chang Xu. Discovery & characterization of a next-generation FGFR4 inhibitor overcoming resistant mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB328.

Epidermal growth factor receptor (EGFR) exon20 insertion mutations and atypical mutations account for about 9% and 20% of EGFR-mutated non-small cell lung cancer (NSCLC), respectively. Currently approved EGFR tyrosine kinase inhibitors (TKIs) have shown efficacy in NSCLC patients with exon20 insertion and atypical mutations, but with limited overall response and high rate of EGFR-related severe adverse events. This may be associated with the inhibition of wild-type (WT) EGFR. ABSK111 is a highly potent, selective, and CNS-penetrable EGFR inhibitor, targeting multiple EGFR and HER2 mutations, including exon20 insertion, atypical, and extracellular mutations. Here we describe the preclinical in vitro and in vivo characterization of ABSK111. ABSK111 potently inhibited the proliferation of BA/F3 cell lines harboring EGFR exon20, atypical and extracellular mutations with higher selectivity for WT EGFR than currently approved EGFR TKIs. ABSK111 also suppressed HER2 atypical and exon20 mutations. Further, ABSK111 potently blocked the phosphorylation of EGFR exon20 insertion mutations and EGFR variant III in BA/F3 cell lines, with less inhibition of WT EGFR signal than the approved TKIs. Moreover, pharmacokinetic and pharmacodynamic studies demonstrated sustained and exposure-dependent suppression of p-ERK in tumor tissue following a single oral dose of ABSK111. Finally, ABSK111 showed dose-dependent anti-tumor activity in BA/F3 tumor models with EGFR exon20 insertion mutations and EGFR variant III without significant body weight loss. Pharmacodynamic analysis of endpoint samples from efficacy study showed sustained inhibition of p-ERK, which was superior to the approved exon20 insertion inhibitor mobocertinib. Taken together, these results demonstrate the ability of ABSK111 to inhibit a broad spectrum of EGFR and HER2 mutations, including exon20 insertions, atypical and extracellular mutations, while sparing the WT form of EGFR. In addition to the application in NSCLC, the activity against EGFR extracellular mutations and the ability to penetrate into brain suggest the application of ABSK111 in glioblastoma multiforme (GBM). Citation Format: Cheng Dai, Juan Peng, Fei Yang, Haibing Deng, Yuan Zhao, Hongping Yu, Yaochang Xu, Zhui Chen, Shuqun Yang. Discovery and characterization of ABSK111, a selective, CNS-penetrable, and broad-spectrum EGFR inhibitor targeting exon20 insertion, atypical and extracellular mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB525.

Summary Background The management of latent Mycobacterium tuberculosis infection is a new priority action for the WHO End Tuberculosis (TB) Strategy. However, national guidelines on latent tuberculosis infection testing and treatment have not yet been developed in China. Here, we present the results from the 2-year follow-up of a study that aimed to track the development of active disease in individuals with latent tuberculosis infection, identify priority populations for latent infection management, and explore the most suitable latent infection diagnostic approach. Methods A population-based multicentre prospective study was done in four sites in rural China, between 2013 and 2015. The baseline survey in 2013 measured the prevalence of latent tuberculosis infection using QuantiFERON-TB Gold In-Tube (QFT) and tuberculin skin test (TST) in eligible participants. During the follow-up phase between 2014–15, we assessed individuals who had tuberculosis infection at baseline (QFT-positivity or TST tuberculin reaction size [induration] of ≥10 mm) for the development of active disease through active case finding. Eligible participants included in follow-up survey had a birth date before June 1, 2008 (5 years or older in 2013), and continuous residence at the study site for 6 months or longer in the past year. Participants with current active tuberculosis at baseline survey were excluded. Findings Between Sept 1, 2013, and Aug 31, 2015, 7505 eligible participants (aged 5 years or older) were included in tuberculosis infection test positive cohorts (4455 were QFT positive, 6404 had TST induration ≥10 mm, and 3354 were positive for both tests) after baseline examination. During the 2-year follow-up period, 84 incident cases of active tuberculosis were diagnosed. Of participants who developed active tuberculosis, 75 were diagnosed with latent infection by QFT, 62 were diagnosed by TST, and 53 were diagnosed by both tests. An incidence rate of 0·87 (95% CI 0·68–1·07) per 100 person-years was observed for individuals who tested positive with QFT, 0·50 (0·38–0·63) per 100 person-years for those who tested positive with TST (p Interpretation Our results suggest that high-risk populations in communities in rural China, such as individuals at a high risk of disease reactivation from previous tuberculosis, should be targeted for latent infection screening and treatment with an interferon-γ releasing assay rather than a TST. Funding National Science and Technology Major Project of China, Program for Changjiang Scholars and Innovative Research Team in University of China, CAMS Innovation Fund for Medical Sciences, and Sanming Project of Medicine in Shenzhen.

Deciphering the combinatorial histone codes has been a long-standing interest in the epigenetics field, which requires the reliable and robust characterization of the post-translational modifications (PTMs) coexisting on histones. To this end, weak cation exchange hydrophilic interaction liquid chromatography is commonly used in middle-down liquid chromatography-mass spectrometry approaches for online separation of variously modified histone peptides. Here we provide a novel strategy that combines the selective histone peptide derivatization using N-hydroxysuccinimide propionate ester with reversed-phase liquid chromatography (RPLC) for the robust, sensitive, and reliable characterization of combinatorial histone PTMs. Derivatization amplifies the subtle physical differences between similarly modified histone peptides, thereby allowing baseline separation of these peptides by standard RPLC. Also, the sensitivity of MS is enhanced greatly by derivatization due to the increased peptide hydrophobicity and concentrated charge-state envelope during electrospray ionization. Furthermore, we systematically optimized the dual electron transfer and higher energy collision dissociation and achieved near-complete peptide sequence coverage in MS/MS spectra, allowing highly precise and reliable PTM identification. Using this method, we identified 311 and 293 combinations of histone H3 PTMs from the lymphoma cells Karpas-422 with/without drug treatment, confirming the advantages of our method in serving as a platform for profiling combinatorial histone PTMs.

Histones participate in epigenetic regulation via a variety of dynamic posttranslational modifications (PTMs) on them. Mass spectrometry (MS) has become a powerful tool to investigate histone PTMs. With the bottom-up mass spectrometry approach, chemical derivatization of histones with propionic anhydride or deuterated acetic anhydride followed by trypsin digestion was widely used to block the hydrophilic lysine residues and generate compatible peptides for LC-MS analysis. However, certain severe side reactions (such as acylation on tyrosine or serine) caused by acid anhydrides will lead to a number of analytical issues such as reducing results accuracy and impairing the reproducibility and sensitivity of MS analysis. As an alternative approach, we report a novel derivatization method that utilizes N-hydroxysuccinimide ester to specifically and efficiently derivatize both free and monomethylated amine groups in histones. A competitive inhibiting strategy was implemented in our method to effectively prevent the side reactions. We demonstrated that our method can achieve excellent specificity and efficiency for histones derivatization in a reproducible manner. Using this derivatization method, we succeeded to quantitatively profile the histone PTMs in KMS11 cell line with selective knock out of translocated NSD2 allele (TKO) and the original parental KMS11 cell lines (PAR) (NSD2, a histone methyltransferase that catalyzes the histone H3 K36 methylation), which revealed a significant crosstalk between H3 protein K27 methylation and adjacent K36 methylation.

The monoterpenoid pheromone (+)-eldanolide, a long range sex attractant, has been synthesized in four steps from the chiral 2,3-epoxy alcohol 4 in 36% overall yield. Our synthetic strategy features the formation of a 1,3-diol by regio- and stereoselective ring opening of 2,3-epoxy alcohol 4, an intermediate easily available from Sharpless asymmetric epoxidation. Other key steps include one carbon elongation, saponification, and lactonization. The present work constitutes a general method for the rapid synthesis of a number of related gamma-lactone natural products. (c) 2007 Elsevier Ltd. All rights reserved.

A propylene oxide assisted base-free Sonogashira cross-coupling reaction has been developed. The unique feature of the current protocol has extended the scope of Sonogashira reaction to some base-sensitive substrates.

A propylene oxide assisted base-free Sonogashira cross-coupling reaction has been developed. The unique feature of the current protocol has extended the scope of Sonogashira reaction to some base-sensitive substrates.

An efficient eight-step assembly of the tetracyclic core (ABCD rings) of ent-(+)-nakadomarin A, a bioactive hexacyclic marine alkaloid, has been realized with Sonogashira coupling, platinum(II)-promoted cascade cyclizations, and saturation of a challenging carbon−carbon double bond through a hydroboration/oxidation/xanthate formation/Barton−McCombie deoxygenation sequence as key transformations.

We have presented two facile four-step syntheses of (±)-tanikolide from ethyl 2-oxocyclopentanecarboxylate. The overall chemical yields of the two sequences reached as high as 76 and 85%, respectively. The first strategy involved alkylation, Baeyer–Villiger reaction, saponification, and reduction/lactonization. The second approach for synthesizing tanikolide took advantage of the same intermediate, the alkylated ketoester 2 , which was converted to the target molecule in such three steps as deethoxycarbonylation, hydroxymethylation, and Baeyer–Villiger reaction. Our strategies are advantageous because of their high yields and suitability for the preparation of 1 in multigram or larger quantities.