JNJ-26854165 - a novel hdm2 antagonist in clinical development showing broad-spectrum preclinical antitumor activity against solid malignancies

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 1592 The Hdm2 oncogene is activated in a variety of cancers through mechanisms including Hdm2 gene amplification, and deletion of tumor suppressors such as p14ARF and PTEN. Hdm2 ubiquitinates p53, resulting in rapid degradation of this tumor suppressor. Hdm2 also regulates a number of other cell cycle proteins thus modulating their activity and stability, such as p73, E2F1, HIF1α and p21 waf1,cip1 . JNJ-26854165 was identified as a novel Hdm2 antagonist with potent antitumor activity against a broad spectrum of solid tumors in preclinical models. JNJ-26854165 induces p53 levels in tumor cell lines, and activates p53 transcriptional activity. However unlike other known Hdm2 antagonists, JNJ-26854165, does not block p53 degradation by displacing p53 from Hdm2, but was found to prevent the association of Hdm2 with the proteasome both in vitro and in cell based assays. JNJ-26854165 potently inhibits proliferation of all main solid tumor cell types, including ovarian, lung, colon, breast and prostate, with IC50 values ranging from 60 nM to 7.7 µM. p53 or Ras mutation status does not affect the antiproliferative effect of the compound. The mechanism through which JNJ-26854165 exerts these antitumor effects in the absence of functional p53 is currently under investigation. JNJ-26854165 has potent oral in vivo antitumor activity in non-small cell lung, breast, colon, prostate and glioblastoma cancer xenograft models at well-tolerated doses. Once daily oral administration JNJ-26854165 leads to regression of subcutaneous U87 glioblastoma tumors, which is accompanied by an increase in p53 positive apoptotic cells in the tumor tissue. JNJ-26854165 also inhibits the growth of Ras and p53 double mutant NCI-H1373 non-small cell lung xenografts to the same extent as Paclitaxel, while Tarceva was inactive. Similarly, growth of PTEN negative orthotopic PC-3 prostate tumors is potently inhibited, to the same extent as with Docetaxel. In summary, JNJ-26854165 represents a novel class of Hdm2 antagonists. The potent activity of JNJ-26854165, regardless of Ras or p53 mutational status, makes JNJ-26854165 a promising first-in-class antitumor agent that may have activity in a broad spectrum of human tumors. JNJ-26854165 is currently in Phase I clinical trials, and is to our knowledge the first Hdm2 antagonist at this advanced stage.