title: A novel lead compound CM-118: antitumor activity and new insight into the molecular mechanism and combination therapy strategy in c-Met- and ALK-dependent cancers.
abstract: The anaplastic lymphoma kinase (ALK) and the c-Met receptor tyrosine kinase play essential roles in the pathogenesis in multiple human cancers and present emerging targets for cancer treatment. Here, we describe CM-118, a novel lead compound displaying low nanomolar biochemical potency against both ALK and c-Met with selectivity over>90 human kinases. CM-118 potently abrogated hepatocyte growth factor (HGF)-induced c-Met phosphorylation and cell migration, phosphorylation of ALK, EML4-ALK, and ALK resistance mutants in transfected cells. CM-118 inhibited proliferation and/or induced apoptosis in multiple c-Met- and ALK-addicted cancer lines with dose response profile correlating target blockade. We show that the CM-118-induced apoptosis in c-Met-amplified H1993 NSCLC cells involved a rapid suppression of c-Met activity and c-Met-to-EGFR cross-talk, and was profoundly potentiated by EGFR inhibitors as shown by the increased levels of apoptotic proteins cleaved-PARP and Bim as well as reduction of the survival protein Mcl-1. Bim-knockdown or Mcl-1 overexpression each significantly attenuated apoptosis. We also revealed a key role by mTOR in mediating CM-118 action against the EML4-ALK-dependent NSCLC cells. Abrogation of EML4-ALK in H2228 cells profoundly reduced signaling capacity of the rapamycin-sensitive mTOR pathway leading to G 1 cell cycle arrest and mitochondrial hyperpolarization, a metabolic perturbation linked to mTOR inhibition. Depletion of mTOR or mTORC1 inhibited H2228 cell growth, and mTOR inhibitors potentiated CM-118's antitumor activity in vitro and in vivo. Oral administration of CM-118 at a wide range of well tolerated dosages diminished c-Met- and ALK phosphorylation in vivo, and caused tumor regression or growth inhibition in multiple c-Met- and ALK-dependent tumor xenografts in mice. CM-118 exhibits favorable pharmacokinetic and drug metabolism properties hence presents a candidate for clinical evaluation.
authors.affiliation: Department of Pharmacology; Fudan University School of Pharmacy; Shanghai, PR China; Department of Nuclear Medicine; Zhongshan Hospital; Fudan University; Shanghai, PR China.
authors.forename: Lanfang
authors.initials: L
authors.lastname: Meng
authors.affiliation: School of Pharmacy; Shanghai Jiaotong University; Shanghai, PR China.
authors.forename: Mengjun
authors.initials: M
authors.lastname: Shu
authors.affiliation: Department of Pharmacology; Fudan University School of Pharmacy; Shanghai, PR China.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Sundia MediTech; Shanghai, PR China.
authors.forename: Dexiao
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Pharmacology; Fudan University School of Pharmacy; Shanghai, PR China.
authors.forename: Qun
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Pharmacology; Fudan University School of Pharmacy; Shanghai, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Sundia MediTech; Shanghai, PR China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Xcovery Inc.; West Palm Beach, FL USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Liang
authors.affiliation: Department of Pharmacology; Fudan University School of Pharmacy; Shanghai, PR China.
authors.forename: Ker
authors.initials: K
authors.lastname: Yu
mesh_terms: D000077716:Afatinib; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology* / Q000627:therapeutic use; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000594646:CM-118; C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D011724:Pyridazines; D011728:Pyridones; D011799:Quinazolines; D000077716:Afatinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; EGFR; c-Met; combination therapy; mTOR; targeted cancer therapy