title: LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models.
abstract: The HGF/MET signaling pathway regulates a wide variety of normal cellular functions that can be subverted to support neoplasia, including cell proliferation, survival, apoptosis, scattering and motility, invasion, and angiogenesis. MET over-expression (with or without gene amplification), aberrant autocrine or paracrine ligand production, and missense MET mutations are mechanisms that lead to activation of the MET pathway in tumors and are associated with poor prognostic outcome. We report here preclinical development of a potent, orally bioavailable, small-molecule inhibitor LY2801653 targeting MET kinase. LY2801653 is a type-II ATP competitive, slow-off inhibitor of MET tyrosine kinase with a dissociation constant (Ki) of 2 nM, a pharmacodynamic residence time (Koff) of 0.00132 min(-1) and t1/2 of 525 min. LY2801653 demonstrated in vitro effects on MET pathway-dependent cell scattering and cell proliferation; in vivo anti-tumor effects in MET amplified (MKN45), MET autocrine (U-87MG, and KP4) and MET over-expressed (H441) xenograft models; and in vivo vessel normalization effects. LY2801653 also maintained potency against 13 MET variants, each bearing a single-point mutation. In subsequent nonclinical characterization, LY2801653 was found to have potent activity against several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, DDR1/2 and against the serine/threonine kinases MKNK1/2. The potential value of MET and other inhibited targets within a number of malignancies (such as colon, bile ducts, and lung) is discussed. LY2801653 is currently in phase 1 clinical testing in patients with advanced cancer (trial I3O-MC-JSBA, NCT01285037).
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, DC0522, 307 E McCarty Street, Indianapolis, IN 46285, USA. s.betty_yan@lilly.com
authors.forename: S Betty
authors.initials: SB
authors.lastname: Yan
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Peek
authors.forename: Rose
authors.initials: R
authors.lastname: Ajamie
authors.forename: Sean G
authors.initials: SG
authors.lastname: Buchanan
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Graff
authors.forename: Steven A
authors.initials: SA
authors.lastname: Heidler
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Hui
authors.forename: Karen L
authors.initials: KL
authors.lastname: Huss
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Konicek
authors.forename: Jason R
authors.initials: JR
authors.lastname: Manro
authors.forename: Chuan
authors.initials: C
authors.lastname: Shih
authors.forename: Julie A
authors.initials: JA
authors.lastname: Stewart
authors.forename: Trent R
authors.initials: TR
authors.lastname: Stewart
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Stout
authors.forename: Mark T
authors.initials: MT
authors.lastname: Uhlik
authors.forename: Suzane L
authors.initials: SL
authors.lastname: Um
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Wu
authors.forename: Lei
authors.initials: L
authors.lastname: Yan
authors.forename: Wei J
authors.initials: WJ
authors.lastname: Yang
authors.forename: Boyu
authors.initials: B
authors.lastname: Zhong
authors.forename: Richard A
authors.initials: RA
authors.lastname: Walgren
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013777:Tetrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D013777:Tetrazoles; D009536:Niacinamide; C586252:merestinib; D019859:Proto-Oncogene Proteins c-met; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases