Jong Sung Koh

G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia

Aberrant activations of Fms-like tyrosine receptor kinase (FLT) 3 are implicated in the pathogenesis of 20% to 30% of patients with acute myeloid leukemia (AML). G-749 is a novel FLT3 inhibitor that showed potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays. G-749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma, FLT3 ligand surge, and stromal protection. Furthermore, it displayed potent antileukemic activity in bone marrow blasts from AML patients regardless of FLT3 mutation status, including those with little or only minor responses to AC220 or PKC412. Oral administration of G-749 yielded complete tumor regression and increased life span in animal models. Thus, G-749 appears to be a promising next-generation drug candidate for the treatment of relapsed and refractory AML patients with various FLT3-ITD/FLT3-TKD mutants and further shows the ability to overcome drug resistance.

Highly potent and selective pyrazolylpyrimidines as Syk kinase inhibitors.

A series of pyrazolylpyrimidine scaffold based Syk inhibitors were synthesized and evaluated for their biological activities and selectivity. Lead optimization efforts provided compounds with potent Syk inhibition in both enzymatic and TNF-α release assay.

Superior efficacy and selectivity of novel small molecule kinase inhibitors of T790M mutant EGFR in preclinical models of lung cancer

The clinical utility of approved EGFR small-molecule kinase inhibitors is plagued both by toxicity against wild-type EGFR and by metastatic progression in the central nervous system, a disease sanctuary site. Here, we report the discovery and preclinical efficacy of GNS-1486 and GNS-1481, two novel small-molecule EGFR kinase inhibitors that are selective for T790M-mutant isoforms of EGFR. Both agents were effective in multiple mouse xenograft models of human lung adenocarcinoma (T790M-positive or -negative), exhibiting less activity against wild-type EGFR than existing approved EGFR kinase inhibitors (including osimertinib). In addition, GNS-1486 showed superior potency against intracranial metastasis of EGFR-mutant lung adenocarcinoma. Our results offer a preclinical proof of concept for new EGFR kinase inhibitors with the potential to improve therapeutic index and efficacy against brain metastases in patients. Cancer Res; 77(5); 1200-11. ©2017 AACR.

Crystal structures of spleen tyrosine kinase in complex with novel inhibitors: structural insights for design of anticancer drugs

Spleen tyrosine kinase (SYK) is a cytosolic nonreceptor protein tyrosine kinase that mediates key signal transduction pathways following the activation of immune cell receptors. SYK regulates cellular events induced by the B‐cell receptor and Fc receptors with high intrinsic activity. Furthermore, SYK has been regarded as an attractive target for the treatment of autoimmune diseases and cancers. Here, we report the crystal structures of SYK in complex with seven newly developed inhibitors (G206, G207, O178, O194, O259, O272, and O282) to provide structural insights into which substituents of the inhibitors and binding regions of SYK are essential for lead compound optimization. Our kinase inhibitors exhibited high inhibitory activities against SYK, with half‐maximal inhibitory concentrations (IC50) of approximately 0.7–33 nm, but they showed dissimilar inhibitory activities against KDR, RET, JAK2, JAK3, and FLT3. Among the seven SYK inhibitors, O272 and O282 exhibited highly specific inhibitions against SYK, whereas O194 exhibited strong inhibition of both SYK and FLT3. Three inhibitors (G206, G207, and O178) more efficiently inhibited FLT3 while still substantially inhibiting SYK activity. The binding mode analysis suggested that a highly selective SYK inhibitor can be developed by optimizing the functional groups that facilitate direct interactions with Asn499.

Crystal structure of pim1 kinase in complex with a pyrido[4,3-d]pyrimidine derivative suggests a unique binding mode.

Human Pim1 kinase is a serine/threonine protein kinase that plays important biological roles in cell survival, apoptosis, proliferation, and differentiation. Moreover, Pim1 is up-regulated in various hematopoietic malignancies and solid tumors. Thus, Pim1 is an attractive target for cancer therapeutics, and there has been growing interest in developing small molecule inhibitors for Pim1. Here, we describe the crystal structure of Pim1 in complex with a newly developed pyrido[4,3-d]pyrimidine-derivative inhibitor (SKI-O-068). Our inhibitor exhibits a half maximum inhibitory concentration (IC50) of 123 (±14) nM and has an unusual binding mode in complex with Pim1 kinase. The interactions between SKI-O-068 and the Pim1 active site pocket residue are different from those of other scaffold inhibitor-bound structures. The binding mode analysis suggests that the SKI-O-068 inhibitor can be improved by introducing functional groups that facilitate direct interaction with Lys67, which aid in the design of an optimized inhibitor.

Abstract C196: A novel selective inhibitor of FLT3 kinase as a therapeutics for AML.

Acute myeloid leukemia (AML) is an aggressive cancer, representing 90% of all adult acute leukemias, with an estimated incidence of 200,000 cases each year worldwide. Noticeably malignant cells, in the majority of AML patients, possess aberrantly expressed FLT3. The corresponding tumor-cell genotyping indicates that 25–30% of the AML blasts carry FLT3 mutations. The molecular characterization of these FLT3 mutations has revealed that they contain either internal tandem duplications (FLT3-ITD) in the juxtamembrane region (17–34%) or point mutations at the kinase domain (7%). Therefore, FLT3 has emerged as a promising target in therapy of AML. The first and second generation of the FLT3 inhibitors such as CEP-701, MLN-518, PKC-412, Sunitinib, Sorafenib, and AC220 are under clinical trial for AML treatment. However, their clinical responses have been below expectation likely due to the influence of plasma inhibitory activity, lack of strong inhibition of downstream effectors involved in aberrant activation of growth pathway, and lack of substantial and sustained inhibition of FLT3 activity, consequently resulting in drug resistance. To address and overcome the key issues leading to several known drug resistances, we have developed a series of novel and highly selective FLT3 inhibitors possessing extreme potency against clinically known FLT3-mutants. One of our leads, SKI-G-801 (G-801), showed IC50 of 0.3 nM for FLT3 and IC50 of 2.1 nM in MV4–11 cells. Furthermore, it also showed IC50 of 3.1 nM in model cell line BaF3 expressing FLT3 D835Y whereas AC220 and PKC412 showed IC50s of 52.4 nM and 11.4 nM in the BaF3 cells, respectively. The tight binding property and the high potency of our lead candidates led to a strong inhibitory activity in the cell model in the presence of human plasma; FLT3 phosphorylation was inhibited by G-801 with IC50 of 9.9nM, while by PKC412 with IC50 of >1000 nM in the human plasma. In addition, a significant tumor regression of 85–100% was observed in a mouse xenograft model using MV4–11 cells by G-801 via oral administration for 28 days. Moreover, a synergistic effect of our lead compounds with AraC was more significant in RS4–11 cells than the known FLT3 inhibitors with AraC. These desirable characteristics of our lead candidates would ostensibly overcome the documented drug resistance confronted by previous FLT3 targeted inhibitors such as AC220, PKC-412, and CEP701. One of our lead candidates is expected to enter preclinical study soon. Therefore, we are confident that our lead candidate will be a promising acute myeloid leukemia drug. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C196.