JNJ-38877605

JNJ-38877605 is a small-molecule ATP-competitive inhibitor of the catalytic activity of c-Met.

Extensive evidence that c-Met signaling is involved in the progression and spread of several cancers and an enhanced understanding of its role in disease have generated considerable interest in c-Met and HGF asmajor targets in anti-cancer drug development.

In vitro: JNJ-38877605 showed ~600-fold selectivity for c-Met compared with a panel of ~250 diverse tyrosine and serine-threonine kinases and was found to potently inhibit HGF-stimulated and constitutively activated c-Met phosphorylation in vitro [1].

In vivo: JNJ-38877605 showed excellent oral bioavailability approaching 100% in all examined species. In addition, JNJ-38877605 in a single dose was observed toinhibit Met phosphorylation in tumor xenografts for up to16 h. Inhibition of Met phosphorylation was associated withdose-dependent tumor growth inhibition using a range of oral dosing regimens [2].

Clinical trial: A Safety and Dose-finding Study of JNJ-38877605 in Patients With Advanced or Refractory Solid Tumors.

Reference:
[1] PereraT, L avrijssenT, Janssens B, et al.  JNJ-38877605: a selective Met kinase inhibitor inducing
regression of Met-driven tumor models.  Presented at the 99th AACR Annual Meeting; 2008 Apr 12 -16;

Effectiveness of inhibitor rapamycin, saracatinib, linsitinib and JNJ-38877605 against human prostate cancer cells.[Pubmed:26131286]

Int J Clin Exp Med. 2015 Apr 15;8(4):6563-7. eCollection 2015.

To investigate the effect of different concentrations of inhibitors rapamycin, saracatinib, linsitinib and JNJ-38877605 on PC-3 cells with CCK-8 assay, respectively. PC-3 cells were incubated with different concentrations of rapamycin, saracatinib, linsitinib and JNJ-38877605, respectively, for 48 h at 37 degrees C, the concentrations of rapamycin were 5 nM, 10 nM, 20 nM, 50 nM, 75 nM, 100 nM; Saracatinib: 0.125 nM, 0.25 nM, 0.5 nM, 1 nM, 2.5 nM, 5 nM; Linsitinib: 2 nM, 5 nM, 10 nM, 20 nM, 40 nM, 60 nM; JNJ-38877605: 0.125 nM, 0.5 nM, 1 nM, 2.5 nM, 5 nM, 10 nM. The proliferation of PC-3 cells was examined by CCK-8. Different concentrations of inhibitor rapamycin remarkably inhibited PC-3 cell proliferation after 48 h (P<0.05), inhibitory action did not change significantly from 5 nM-100 nM; different concentrations of saracatinib, linsitinib and JNJ-38877605 did not inhibit PC-3 cell proliferation after 48 h. Rapamycin treatment at low concentration can inhibit the proliferation of PC-3 cells, while saracatinib, linsitinib and JNJ-38877605 do not inhibit PC-3 cell proliferation.

The c-Met Tyrosine Kinase Inhibitor JNJ-38877605 Causes Renal Toxicity through Species-Specific Insoluble Metabolite Formation.[Pubmed:25745036]

Clin Cancer Res. 2015 May 15;21(10):2297-2304.

PURPOSE: The receptor tyrosine kinase c-Met plays an important role in tumorigenesis and is a novel target for anticancer treatment. This phase I, first-in-human trial, explored safety, pharmacokinetics, pharmacodynamics, and initial antitumor activity of JNJ-38877605, a potent and selective c-Met inhibitor. EXPERIMENTAL DESIGN: We performed a phase I dose-escalation study according to the standard 3+3 design. RESULTS: Even at subtherapeutic doses, mild though recurrent renal toxicity was observed in virtually all patients. Renal toxicity had not been observed in preclinical studies in rats and dogs. Additional preclinical studies pointed toward the rabbit as a suitable toxicology model, as the formation of the M10 metabolite of JNJ-38877605 specifically occurred in rabbits and humans. Additional toxicology studies in rabbits clearly demonstrated that JNJ-38877605 induced species-specific renal toxicity. Histopathological evaluation in rabbits revealed renal crystal formation with degenerative and inflammatory changes. Identification of the components of these renal crystals revealed M1/3 and M5/6 metabolites. Accordingly, it was found that humans and rabbits showed significantly increased systemic exposure to these metabolites relative to other species. These main culprit insoluble metabolites were generated by aldehyde oxidase activity. Alternative dosing schedules of JNJ-3877605 and concomitant probenecid administration in rabbits failed to prevent renal toxicity at dose levels that could be pharmacologically active. CONCLUSIONS: Combined clinical and correlative preclinical studies suggest that renal toxicity of JNJ-38877605 is caused by the formation of species-specific insoluble metabolites. These observations preclude further clinical development of JNJ-38877605.

JNJ-38877605 is an ATP-competitive inhibitor of c-Met with IC50 of 4 nM, 600-fold selective for c-Met than 200 other tyrosine and serine-threonine kinases.

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