Chang-Soo Yun

Novel bis-ortho-alkoxy-para-piperazinesubstituted-2,4-dianilinopyrimidines (KRCA-0008) as potent and selective ALK inhibitors for anticancer treatment

The synthesis of bis-ortho-alkoxy-para-piperazinesubstituted-2,4-dianilinopyrimidines is described and their structure-activity-relationship to anaplastic lymphoma kinase (ALK) is presented. KRCA-0008 is selective and potent to ALK and Ack1, and displays drug-like properties without hERG liability. KRCA-0008 demonstrates in vivo efficacy comparable to Crizotinib in xenograft mice model.

Discovery of substituted 6-pheny-3H-pyridazin-3-one derivatives as novel c-Met kinase inhibitors.

We report a series of phenyl substituted pyridazin-3-ones substituted with morpholino-pyrimidines. The SAR of the phenyl was explored and their c-Met kinase and cell-based inhibitory activity toward c-Met driven cell lines were evaluated. Described herein is a potent c-Met inhibitor by structural modification of the parent morpholino-pyridazinone scaffold, with particular focus on the phenyl and pyrimidine substituents.

Discovery of novel tetrahydroisoquinoline-containing pyrimidines as ALK inhibitors.

Exploration of the two-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs) led to discovery of 8 and 17 as highly potent ALK inhibitors. THIQs 8 and 17 showed encouraging in vitro and in vivo xenograft efficacies, comparable with those of LDK378. Although THIQ analogs (8a-o and 17a-i) prepared were not as active as their parent compounds, both 8 and 17 have significant inhibitory activities against various ALK mutant enzymes including G1202R, indicating that this series of compounds could be further optimized as useful ALK inhibitors overcoming the resistance issues found from crizotinib and LDK378.

Minor modifications to ceritinib enhance anti-tumor activity in EML4-ALK positive cancer

Ceritinib, an ALK inhibitor, was hurriedly approved by the US FDA last year, and demonstrates impressive results in EML4-ALK positive patients. To get a superior ALK inhibitor, we synthesized several ceritinib derivatives with minor modifications to the phenylpiperidine moiety. Biochemical and cellular assays demonstrated the improved activity of KRCA-386 over that of ceritinib. KRCA-386 has superior inhibitory activity against ALK mutants commonly found in crizotinib-resistant patients. Particularly, KRCA-386 has considerably greater activity than ceritinib against the G1202R mutant, one of the most challenging mutations to overcome. The cell cycle analysis indicates that ALK inhibitors induce G1/S arrest, resulting in apoptosis. The in vivo xenograft data also demonstrate that KRCA-386 is significantly better than ceritinib. KRCA-386 dosed at 25 mpk caused 105% tumor growth inhibition (TGI) compared to 72% TGI with ceritinib dosed at 25 mpk. (n = 8, P = 0.010) The kinase profiling assay revealed that several kinases, which are known to be critical for tumor growth, are inhibited by KRCA-386, but not by ceritinib. We anticipate that this characteristic of KRCA-386 enhances its in vivo efficacy. In addition, KRCA-386 shows excellent blood brain barrier penetration compared to ceritinib. These results suggest that KRCA-386 could be useful for crizotinib-resistant patients with brain metastases.

Novel 2,4-dianilino-5-fluoropyrimidine derivatives possessing ALK inhibitory activities

A new series of 2,4-dianilino-5-fluoropyrimidine derivatives were designed and synthesized and their anaplastic lymphoma kinase (ALK) inhibitory activities were evaluated by biochemical and cell-based assays in order to discover a new ALK inhibitor. Most compounds synthesized showed good inhibitory activities against ALK and good cytotoxic activities in H3122 cell line. The best compound 6f showed good activity against wild-type ALK along with crizotinib-resistant mutant ALK, and it showed 6 times better activity in cell-based assay than crizotinib. Some SAR studies were performed by the comparisons of the activities between 6 and the designed-synthesized compounds.

Discovery of substituted pyrazol-4-yl pyridazinone derivatives as novel c-Met kinase inhibitors

A series of pyridazin-3-one substituted with morpholino-pyrimidine derivatives was synthesized and evaluated as tyrosine kinase inhibitors against c-Met enzyme, and anti-proliferative activities of Hs746T human gastric cancer cell line. Most of compounds exhibited good biological activity, while compound 10, 12a, 14a displayed excellent c-Met enzyme inhibitory activities and Hs746T cell-based activities.

Abstract A287: Discovery of c-Met kinase inhibitors for anticancer therapeutics.

c-Met recepter tyrosine kinase (RTK) and its ligand, hepatocyte growth factor (HGF), have been reported to be involved in tumorigenesis and metastatic progression. Also, aberrant c-Met signaling has been reported in a wide variety of cancers such as gastric, lung, colon, breast, bladder, head and neck, ovarian, prostate, thyroid, pancreatic, hematological malignancies, and central nervous system tumors. We have synthesized a series of triazolopyridazine derivatives and their c-Met (mesenchymal-epithelial transition factor) inhibitory activities have been evaluated. A potent c-Met kinase inhibitor by structural modification of the parent pyrimidine scaffold with particular focus on the aryl substituent on the triazolopyridazines will be discussed. Several triazolopyridazine derivatives were found to be potent as c-Met inhibitors in enzyme assays and cell-based assays (c-Met addicted cell lines). We found KRC-00831 is a highly potent and selective c-Met receptor tyrosine kinase inhibitor over other kinases (c-Met enzyme, IC50=3 nM) and exhibit excellent cellular activities in c-Met driven cell lines (Hs746T, GI50=0.1 nM; H1993, GI50=27 nM, MKN45, GI50=15 nM; SNU-5, GI50=8 nM). KRC-00831 is chemically and metabolically very stable and showed no CYP inhibition, hERG binding activity. KRC-00831 strongly suppressed the growth of c-Met over-expressed cancer cells, while not in c-Met absent cancer cell lines. In xenograft animal models, we observed not only dose dependent tumor growth inhibitions but complete tumor regressions. In summary, we suggest that KRC-00831 wil be a novel drug candidate with the therapeutic potential of targeting c-Met in human cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A287. Citation Format: Chang-Soo Yun, Sung Yun Cho, Hyoung Rae Kim, Hee Jung Jung, Jae Du Ha, Kwangho Lee, Pilho Kim, Chi Hoon Park, Chong Ock Lee. Discovery of c-Met kinase inhibitors for anticancer therapeutics. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A287.

Abstract A284: Anaplastic lymphoma kinase (ALK) inhibitors for cancer treatment.

Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, has been recently elucidated as a potential target for various cancers due to its implications of tumorigenesis by ALK gene mutations, overexpressions, and amplifications. ALK was first identified in 1994 as a part of nucleophosmin NPM-ALK fusion gene in 60% of anaplastic large-cell lymphoma (ALCL). In late 2007, EML4-ALK fusion gene was found in 3∼7% of non-small cell lung cancer (NSCLC), and a kind of ALK fusion genes are found one by one in various cancers such as DLBCL, inflammatory myofiblastic tumor (IMT), plasmacytoma, esophageal cancer, and ovarian cancer. More over mutated ALK is much implicated in neuroblastoma and thyroid carcinoma. Crizotinib (Xalkori) was the first small molecule inhibitor which was approved as a treatment of NSCLC including ALK fusion gene by FDA in 2011. Crizotinib, a potent inhibitor of both c-Met and ALK tyrosine kinases is a 3-benzyloxy-2-aminopyridine derivative derived from c-Met inhibitors and surprisingly its overall clinical benefit was 57 %. However, its clinical efficacy is limited by drug-resistance mutations, particularly the gatekeeper L1196M mutation. Unlike their aminopyridine-based core scaffold, a pyrimidine-based inhibitor has been identified for the ALK-related inhibition and shown a potent activity to EML4-ALK wild type and other mutants including EML4-ALK L1196M. In this paper, we designed and synthesized a new series of pyrimidine derivatives to discover a new ALK inhibitor which is well-matched with crizotinib and LDK378 in docking study. KRCA-0008 has been identified as a highly potent and selective ALK inhibitor with potency profiles (ALK wt, IC50=12 nM). It has excellent activities both ALK mutants (L1196M, C1156Y, F1174L, R1275Q) and BaF3 ALK L1196M cell line. PK profiles were excellent and KRCA-0008 was safe in Ames test, chromosomal aberration assay, micronucleus asssay, and acute toxicity. Also, we observed KRCA-0008 is chemically and metabolically very stable and no CYP and hERG inhibitions. In vivo xenograft mouse model (H3122 NSCLC) model study, KRCA-0008 shows moderate tumor growth inhibition without significant body weight change. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A284. Citation Format: Kwangho Lee, Hyoung Rae Kim, Sung Yun Cho, Hee Jung Jung, Jae Du Ha, Chang-Soo Yun, Pilho Kim, Chi Hoon Park, Chong Ock Lee. Anaplastic lymphoma kinase (ALK) inhibitors for cancer treatment. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A284.