Abstract 4791: OMO-1, a potent, highly selective, orally bioavailable, MET kinase inhibitor with a favorable preclinical toxicity profile, shows both monotherapy activity, against MET pathway-driven tumors, and EGFR TKI combination activity in acquired resistance models

Abstract

Activation of the MET/HGF pathway has been linked to tumor initiation, metastasis, angiogenesis and resistance to therapeutic agents. Here we present pharmacological characterization of OMO-1 (formerly JNJ-38877618), a potent, highly selective, orally bioavailable MET kinase inhibitor with nM binding affinity (Kd=1.4 nM) and enzyme inhibitory activity against wt and M1268T mutant MET (2 and 3 nM IC50). MET inhibitory effects were assessed in proliferation, colony formation and motility assays. OMO-1 displayed nM potency against MET Ampl/mutant and therapy resistant models. In vivo, OMO-1 induced complete inhibition of tumor growth in 3 models: the SNU5 MET amp gastric, U87-MG HGF autocrine glioblastoma and Hs746T MET exon 14 skipping mutant gastric cancer. OMO-1 induced regression of large MET amplified EBC-1 SqNSCLC where OMO-1 led to dose- and time-dependent inhibition of MET kinase activation, with the duration of target shut down considerably exceeding plasma exposure times. Combination treatments were well tolerated and improved EGFR targeted therapy. Although single agent OMO-1 had no effect on NSCLC HCC827 EGFR, combination with Erlotinib led to delayed onset of tumor recurrence. The acquired EGFR inhibitor resistant model HCC827-ER1 was determined to be MET amplified. OMO-1 and erlotinib both inhibited tumor growth of this model whilst combination induced tumor regression. In an EGFR inhibitor resistant PDX having MET amplification, single agent OMO-1 caused tumour stasis whereas MetMab/erlotinib only led to tumor growth delay. The potent preclinical activity we have observed, supports ongoing clinical development of OMO-1 in patients with MET pathway-driven tumors. Citation Format: Marion Libouban, Eleonora Jovcehva, Desiree De Lange, Boudewijn Janssens, Tinne Verhulst, Souichi Ogata, Berthold Wroblowski, Laurence Mevellec, Tianbao Lu, Glen Clack, Timothy Perera. OMO-1, a potent, highly selective, orally bioavailable, MET kinase inhibitor with a favorable preclinical toxicity profile, shows both monotherapy activity, against MET pathway-driven tumors, and EGFR TKI combination activity in acquired resistance models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4791.

OMO-1 reduces progression and enhances cisplatin efficacy in a 4T1-based non-c-MET addicted intraductal mouse model for triple-negative breast cancer

“…Crizotinib and cabozantinib, for example, showed promising results in TNBC preclinical models and patients [9][10][11][12] . A recently developed highly selective ATP-competitive c-MET inhibitor OMO-1 (formerly referred to as JNJ-38877618, chemical structure: 6-(difluoro(6-(pyridin-4-yl) 1,2,4 triazolo [4,3-b]pyridazin-3-yl)methyl) quinoline) has also raised attention as an alternative agent 1,13 . More specifically, preclinical studies with OMO-1 showed its superior inhibitory activity against wild-type c-MET compared to crizotinib (i.e., 2 versus 11.7 nM IC 50 ) 13 .…”

“…A recently developed highly selective ATP-competitive c-MET inhibitor OMO-1 (formerly referred to as JNJ-38877618, chemical structure: 6-(difluoro(6-(pyridin-4-yl) 1,2,4 triazolo [4,3-b]pyridazin-3-yl)methyl) quinoline) has also raised attention as an alternative agent 1,13 . More specifically, preclinical studies with OMO-1 showed its superior inhibitory activity against wild-type c-MET compared to crizotinib (i.e., 2 versus 11.7 nM IC 50 ) 13 . A phase I/II clinical trial (NCT03138083) evaluated the safety, tolerability, and preliminary therapeutic efficacy of OMO-1 in c-MET pathway-driven solid tumors 13,14 .…”

“…More specifically, preclinical studies with OMO-1 showed its superior inhibitory activity against wild-type c-MET compared to crizotinib (i.e., 2 versus 11.7 nM IC 50 ) 13 . A phase I/II clinical trial (NCT03138083) evaluated the safety, tolerability, and preliminary therapeutic efficacy of OMO-1 in c-MET pathway-driven solid tumors 13,14 . Nevertheless, the efficacy of OMO-1 in TNBC has not yet been investigated preclinically.…”

A Phase I Trial of the Dual MET Kinase/OCT-2 Inhibitor OMO-1 in Metastatic Solid Malignancies Including MET Exon 14 Mutated Lung Cancer

“…In preclinical studies, OMO-1 leads to complete inhibition of tumor growth in diverse in vivo MET-activated tumor models. 21 In addition, in EGFR TKI-resistant models with MET amplification, the combination of erlotinib and OMO-1 induced tumor regression. 21 In addition to MET inhibition, OMO-1 was identified as a potent inhibitor of the organic cation transporter 2 (OCT-2), which is involved in the active secretion of creatinine and tryptophan.…”

“… 21 In addition, in EGFR TKI-resistant models with MET amplification, the combination of erlotinib and OMO-1 induced tumor regression. 21 In addition to MET inhibition, OMO-1 was identified as a potent inhibitor of the organic cation transporter 2 (OCT-2), which is involved in the active secretion of creatinine and tryptophan. 22 The suppressed OCT-2 mediated secretion of tryptophan might lead to increased plasma levels of tryptophan, thereby stimulating T-cell proliferation and differentiation.…”