JNJ-26481585: A novel “second-generation” oral pan-Histone Deacetylase (HDAC) inhibitor showing broad-spectrum preclinical antitumor activity against solid and haematological malignancies

Abstract

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Histone deacetylase (HDAC) inhibitors have shown promising clinical activity in the treatment of haematological malignancies, resulting in the recent approval of Vorinostat (SAHA) for the treatment of Cutaneous T-Cell Lymphoma. We previously identified R306465 as a highly potent class-I selective HDAC inhibitor, showing oral preclinical antitumor activity (Arts et al., 2007). Pharmacodynamic studies revealed that, like most HDAC inhibitors in clinical development, R306465 only transiently induces histone acetylation in tumor tissue. To identify novel HDAC inhibitors with superior pharmacodynamic properties, we developed an animal model allowing non-invasive real-time evaluation of response (Beliën et al., 2006). In vivo pharmacodynamic analysis of 140 potent pyrimidyl-hydroxamic acid analogues resulted in the identification of JNJ-26481585, a novel “second generation” oral pan-HDAC inhibitor with broad-spectrum preclinical antitumor activity. Pharmacodynamic analysis shows that once daily oral administration of JNJ-26481585 induces continuous histone H3 acetylation in human HCT116 colon tumors, resulting in complete tumor growth inhibition. Similarly, JNJ-26481585 completely inhibits tumor growth in both human ER-/PR-/Her2-negative MDA-MB-231 breast carcinoma, and in human K-ras mutant A549 non small cell lung carcinoma (NSCLC) tumor models with observed efficacy greater than Paclitaxel. JNJ-26481585, is a potent pan-HDAC inhibitor (HDAC1, IC₅₀ 0.16 nM) and induces acetylation of both HDAC1 (histones) and HDAC6 substrates (Tubulin) in A2780 cells. JNJ-26481585 inhibits tumor cell proliferation (IC₅₀ values 2 to 144 nM) and induces widespread apoptosis in all tumor cell lines tested regardless of p53 or Ras mutational status. Patient-derived, Adriamycin-resistant, breast carcinoma cells and Paclitaxel-resistant NSCLC cells are also highly sensitive to JNJ-26481585. The potent single agent antitumor activity in preclinical models combined with its favourable pharmacodynamic profile, makes JNJ-26481585 a promising “second generation” HDAC inhibitor with potential applicability in a broad spectrum of human solid and haematological malignancies. JNJ-26481585 is currently in Phase I clinical trials.