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Targeting mutated EGFR is a clinically validated approach for tackling non-small cell lung cancer (NSCLC). Approximately 20% of patients with advanced NSCLC harbor an EGFR mutation. Osimertinib is a 3rd-generation oral EGFR-TKI targeting the EGFR sensitizing mutations Del19 and L858R, as well as an acquired mutation, T790M. Despite osimertinib's efficacy in NSCLC, resistance develops and the mechanisms of resistance to osimertinib are complex. Development of another mutation, C797S is the most common mechanism of acquired resistance following osimertinib treatment. This mutation occurs with about 12% frequency after a 1L therapy of osimertinib, and with approximately 17% frequency after a 2L therapy. Here, we report TRX-221 as a novel 4th-generation EGFR-TKI that can overcome C797S-mediated acquired resistance in NSCLC models in vitro and in vivo. TRX-221 exhibited potent inhibitory activity against multiple EGFR mutant kinases, including Del19/T790M/C797S, L858R/T790M/C797S, Del19/C797S, L858R/C797S, Del19/T790M, L858R/T790M, Del19, and L858R. Likewise, TRX-221 potently inhibited the proliferation of Ba/F3 cells stably overexpressing these eight EGFR mutants. TRX-221 however showed sparing activity against EGFR wild-type kinase and cell lines. TRX-221 also demonstrated marked anti-proliferative activity against osimertinib-resistant patient-derived cancer cell lines (PDCs). With favorable DMPK profiles, once-daily oral dosing of TRX-221 induced strong anti-tumor effects in a dose-dependent manner in a variety of osimertinib-resistant CDX and PDX models. As a reversible, selective, and broad-spectrum 4th-generation EGFR-TKI, TRX-221 is currently undergoing IND-enabling studies and shows strong potential as a therapeutic solution to treat advanced NSCLC patients harboring EGFR mutations. Citation Format: Sumin Lim, Seulgi Choi, Ju-Kyung Lee, Eunhyun Choi, Sungwon Lee, Kwangwoo Chun, Myoungki Baek, Jiyeon Park, Jihyun Kim, Areum Kang, Younghoon Kim, Namkyoung Kim, Byoungchul Cho, Taebo Sim, Koo Lee. TRX-221, a novel 4th-generation EGFR inhibitor for overcoming C797S mutation-mediated acquired resistance in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4006.

New potent glycogen synthase kinase-3 (GSK-3) inhibitors, 8-amino-[1,2,4]triazolo[4,3- a ]pyridin-3(2 H )-one derivatives, were designed by modeling, synthesized and evaluated in vitro . Compound 17c showed good potency in enzyme and cell-based assays (IC 50 = 111 nM, EC 50 = 1.78 μM). Moreover, it has demonstrated desirable water solubility, PK profile, and moderate brain penetration.

A series of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors, 5-oxo-2,4,5,6-tetrahydro-1H-thiopyrano[3,4-c]quinoline-9-carboxamide derivatives, were successfully synthesized and their PARP-1 inhibitory activity was evaluated. These compounds were prepared from carboxylic acid 7 and the appropriate amines, and a number of the synthesized compounds were found to have significant PARP-1 activity. Among them, 9m showed potent activity in a PARP-1 enzymatic assay and cell-based assay (IC50 = 0.045 μM, ED50 = 0.54 μM). Molecular modeling studies confirmed the obtained biological results.

Graduate Program in Biomaterials Science and Engineering, Yonsei University, Seoul 120-740, KoreaReceived February 24, 2011, Accepted March 31, 2011A series of potent tricyclic derivatives with a non-aromatic amide as potent PARP-1 inhibitors weresuccessfully synthesized and their PARP-1 inhibitory activity was evaluated. Among the derivatives, 2-(1-propylpiperidin-4-yloxy)-7,8,9,10-tetrahydrophenanthridin-6(5 H)-one 23c displayed potent activity in aPARP-1 enzymatic assay and cell-based assay (IC

A series of coumarin based TACE inhibitors were designed to bind in S1' pocket of TACE enzyme based on their docking study. Twelve analogues were synthesized and most of compounds were active in vitro TACE enzyme inhibition as well as cellular TNF-α inhibition. Among these, 15l effectively inhibited the production of serum TNF-α by oral administration at a dose of 30 mg/kg. Compound 15l also showed a good oral bioavailability at 42% and effectively inhibited paw edema in rat carrageenan model. Quantitative structure-activity relationship (QSAR) study using genetic function approximation technique (GFA) and docking study were performed to confirm the series of coumarin core TACE inhibitors. QSAR model have been evaluated internally and externally using test set prediction. Through docking study of each molecule, it is validated that the electrostatic descriptors from the QSAR equation could explain the importance of S1' pocket and the TACE inhibitory activity well.

A series of coumarin types MMP inhibitors were designed based on gelastatin hydroxamates (1) and evaluated for TACE, cellular TNF-α, and NO inhibitory activities. Among them, compounds 9b had potent inhibitory activities in enzymatic and cellular assays and good selectivity to MMP-2 and MMP-9. Further investigation of 9b will be carried out for its efficacy in RA animal model system.

New thiocolchicine derivatives (1-8) were designed as less toxic anticancer agents possessing the power full anticancer activity of colchicine. The synthesis and biological evaluation of these compounds were described. As a preliminary result of biological in vitro investigation, compounds 1, 6, and 7 showed lower toxicities than that of colchicine in combination with potent anticancer activities.

Inactivation of the NF-κB signaling pathway by inhibition of IKKβ is a well-known approach to treat inflammatory diseases such as rheumatoid arthritis and cancer. Thienopyrimidine-based analogues were designed through modification of the known IKKβ inhibitor, SPC-839, and then biologically evaluated. The resulting analogues had good inhibitory activity against both nitric oxide and TNF-α, which are well-known inflammatory responses generated by activated NF-κB. However, no inhibitory activity against IKKβ was observed with these compounds. The thienopyrimidine-based analogues were subsequently screened for a target kinase, and FLT3, which is a potential target for acute myeloid leukemia (AML), was identified. Thienopyrimidine-based FLT3 inhibitors showed good inhibition profiles against FLT3 under 1μM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML.

A highly stereocontrolled synthesis of 3 was accomplished. This involves the conversion of the cyclic intermediate 5 (from the reaction of dihydropyran 1 with aldehyde promoted by Lewis acid catalyst) to 6 in the presence of bases and introduction of an ester functionality from hydrolysis of the ortho ester intermediate. The method described herein is successful with a variety of aldehydes and affords products in high yields (55–89%) with useful levels of diastereoselectivity (10–30∶1). Experiments are described which unambiguously established the stereochemistry for the coupling products. Synthetic manipulations of products by functional group transformations to useful compounds are also reported.

Glycogen synthase kinase-3 (GSK-3) is emerging as a prominent therapeutic target of Alzheimer’s disease (AD). A number of studies have been undertaken to develop GSK-3 inhibitors for clinical use. We report two novel GSK-3 inhibitors (C-7a and C-7b) showing good activity and pharmacokinetic (PK) profiles. IC 50 of new GSK-3 inhibitors were in the range of 120–130 nM, and they effectively reduced the Aβ-oligomers induced neuronal toxicity. Also, new GSK-3 inhibitors decreased the phosphorylated tau at pThr231, pSer396, pThr181, and pSer202, and inhibited the GSK-3 activity against Aβ-oligomers induced neuronal cell toxicity. In B6;129- Psen1 tm1Mpm Tg(APPSwe, tauP301L)1Lfa/Mmjax model of AD, oral administration of C-7a (20 mg/kg, 50 mg/kg) showed increased total arm entries and spontaneous alteration of Y -maze which was regarded as short-term memory. In particular, 50 mg/kg C-7a treated mice significantly decreased the level of phosphorylated tau (Ser396) in brain hippocampus. We suggest that new GSK-3 inhibitor (C-7a) is potential candidates for the treatment of AD.

Graduate Program in Biomaterials Science and Engineering, Yonsei University, Seoul 120-740, KoreaReceived February 24, 2011, Accepted March 31, 2011A series of potent tricyclic derivatives with a non-aromatic amide as potent PARP-1 inhibitors weresuccessfully synthesized and their PARP-1 inhibitory activity was evaluated. Among the derivatives, 2-(1-propylpiperidin-4-yloxy)-7,8,9,10-tetrahydrophenanthridin-6(5 H)-one 23c displayed potent activity in aPARP-1 enzymatic assay and cell-based assay (IC

Highly potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors, including 9-hydroxy-1,2-dihydro-4H-thiopyrano[3,4-c]quinolin-5(6H)-one derivatives with a non-aromatic A-ring, were synthesized. Among the derivatives, 12a showed low nanomolar enzyme and cellular activity (IC(50) = 42 nM, ED(50) = 220 nM) with good water solubility. Further, 12a exhibited microsomal stability in vitro and brain permeability in vivo.