Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors

// Bruce W. Konicek 1 , Andrew R. Capen 1 , Kelly M. Credille 1 , Philip J. Ebert 1 , Beverly L. Falcon 1 , Gary L. Heady 1 , Bharvin K.R. Patel 1 , Victoria L. Peek 1 , Jennifer R. Stephens 1 , Julie A. Stewart 1 , Stephanie L. Stout 1 , David E. Timm 1 , Suzane L. Um 1 , Melinda D. Willard 1 , Isabella H. Wulur 1 , Yi Zeng 1 , Yong Wang 1 , Richard A. Walgren 1 and Sau-Chi Betty Yan 1 1 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA Correspondence to: Bruce W. Konicek, email: konicek_bruce_w@lilly.com Keywords: NTRK fusion; merestinib; LY2801653; NTRK inhibitor; type II kinase inhibitor Received: October 19, 2017     Accepted: January 31, 2018     Published: February 13, 2018 ABSTRACT Merestinib is an oral multi-kinase inhibitor targeting a limited number of oncokinases including MET, AXL, RON and MKNK1/2. Here, we report that merestinib inhibits neurotrophic receptor tyrosine kinases NTRK1/2/3 which are oncogenic drivers in tumors bearing NTRK fusion resulting from chromosomal rearrangements. Merestinib is shown to be a type II NTRK1 kinase inhibitor as determined by x-ray crystallography. In KM-12 cells harboring TPM3-NTRK1 fusion, merestinib exhibits potent p-NTRK1 inhibition in vitro by western blot and elicits an anti-proliferative response in two- and three-dimensional growth. Merestinib treatment demonstrated profound tumor growth inhibition in in vivo cancer models harboring either a TPM3-NTRK1 or an ETV6-NTRK3 gene fusion. To recapitulate resistance observed from type I NTRK kinase inhibitors entrectinib and larotrectinib, we generated NIH-3T3 cells exogenously expressing TPM3-NTRK1 wild-type, or acquired mutations G595R and G667C in vitro and in vivo . Merestinib blocks tumor growth of both wild-type and mutant G667C TPM3-NTRK1 expressing NIH-3T3 cell-derived tumors. These preclinical data support the clinical evaluation of merestinib, a type II NTRK kinase inhibitor (NCT02920996), both in treatment naive patients and in patients progressed on type I NTRK kinase inhibitors with acquired secondary G667C mutation in NTRK fusion bearing tumors.