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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.

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.