Conclusions:The potent antitumor activity as a single agent in preclinical models combined with its favorable pharmacodynamic profile makes JNJ-26481585 a promising "second-generation" HDAC inhibitor. The compound is currently in clinical studies, to evaluate its potential applicability in a broad spectrum of both solid and hematologic malignancies. (Clin Cancer Res 2009;15(22):6841-51)

R306465 is a novel hydroxamate-based histone deacetylase (HDAC) inhibitor with broad-spectrum antitumour activity against solid and haematological malignancies in preclinical models. R306465 was found to be a potent inhibitor of HDAC1 and -8 (class I) in vitro. It rapidly induced histone 3 (H3) acetylation and strongly upregulated expression of p21 waf1,cip1 , a downstream component of HDAC1 signalling, in A2780 ovarian carcinoma cells. R306465 showed class I HDAC isotype selectivity as evidenced by poor inhibition of HDAC6 (class IIb) confirmed by the absence of downregulation of Hsp90 chaperone c-raf protein expression and tubulin acetylation. This distinguished it from other HDAC inhibitors currently in clinical development that were either more potent towards HDAC6 (e.g. vorinostat) or had a broader HDAC inhibition spectrum (e.g. panobinostat). R306465 potently inhibited cell proliferation of all main solid tumour indications, including ovarian, lung, colon, breast and prostate cancer cell lines, with IC 50 values ranging from 30 to 300 nM. Haematological cell lines, including acute lymphoblastic leukaemia, acute myeloid leukaemia, chronic lymphoblastic leukaemia, chronic myeloid leukaemia, lymphoma and myeloma, were potently inhibited at a similar concentration range. R306465 induced apoptosis and inhibited angiogenesis in cell-based assays and had potent oral in vivo antitumoral activity in xenograft models. Once-daily oral administration of R306465 at well-tolerated doses inhibited the growth of A2780 ovarian, H460 lung and HCT116 colon carcinomas in immunodeficient mice. The high activity of R306465 in cell-based assays and in vivo after oral administration makes R306465 a promising novel antitumoral agent with potential applicability in a broad spectrum of human malignancies.

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Real-time analysis of gene expression in experimental tumor models represents a major tool to document disease biology and evaluate disease treatment. However, monitoring gene regulation in vivo still is an emerging field, and thus far it has not been linked to long-term tumor growth and disease outcome. In this report, we describe the development and validation of a fluorescence-based gene expression model driven by the promoter of the cyclindependent kinase inhibitor p21 waf1,cip1 . The latter is a key regulator of tumor cell proliferation and a major determinant in the response to many anticancer agents such as histone deacetylase inhibitors. In response to histone deacetylase inhibitors, induction of fluorescence in A2780 ovarian tumors could be monitored in living mice in a noninvasive real-time manner using whole-body imaging. Single p.o. administration of the histone deacetylase inhibitor MS-275 significantly induces tumor fluorescence in a time-and dose-dependent manner, which accurately predicted long-term antitumoral efficacy in individual mice following extended treatment. These findings illustrate that this technology allows monitoring of the biological response induced by treatment with histone deacetylase inhibitors. In addition to providing experimental pharmacokinetic/pharmacodynamic markers for investigational drugs, this model provides insight into the kinetics of in vivo regulation of transcription, which plays a key role in causing and maintaining the uncontrolled proliferation of tumor tissue. [Mol Cancer Ther 2006;5(9):2317 -23]

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Aberrant DNA methylation patterns are a prominent feature of cancer. Methylation of DNA is mediated by the DNA methyltransferase (DNMT) protein family, which regulates de novo (DNMT3A and DNMT3B) and maintenance (DNMT1) methylation. Mutations in DNMT3A are observed in approximately 22% of acute myeloid leukemia (AML). We hypothesized that DNMT1 or DNMT3B could function as a synthetic lethal therapeutic strategy for DNMT3A-mutant AML. CRISPR-Cas9 tiling screens were performed to identify functional domains within DNMT1/DNMT3B that exhibited greater dependencies in DNMT3A mutant versus wild-type cell lines. Although increased sensitivity to DNMT1 mutation was observed in some DNMT3A mutant cellular models tested, the subtlety of these results prevents us from basing any conclusions on a synthetic lethal relationship between DNMT1 and DNMT3A. Our data suggests that a therapeutic window for DNMT1 methyltransferase inhibition in DNMT3A-driven AML may exist, but validation in more biologically relevant models is required.

JNJ-26481585 is a promising “second generation” oral pan-HDAC inhibitor. Recently, we have published data describing the identification and characterization of the molecule as a potent inhibitor of HDAC1 with a favorable pharmacodynamic profile. Subsequent analysis has shown that the compound has pan-HDAC inhibitory activity and demonstrates effective inhibition of tumor cell growth across a broad spectrum of solid and hematological tumor cell lines. Recent data has also shown that in vivo JNJ-26481585 alone, or in combination with bortezomib, is an effective agent in myeloma. Herein we describe the activity of JNJ-26481585 against a broad range of preclinical solid tumor xenograft models, at doses substantially below MTD and with different schedules of administration in order to address the clinical utility of this agent. Significant growth inhibition was achieved when dosing JNJ-26481585 at MTD with T/C in tumors of; A2780 ovarian tumor xenograft (3%), ras-mutant colon (HCT-116), (7%), MDA-MB-231 breast (38%), DU-145 prostate (11%) and lung H460, A549 and ras mutant NCI-H1373 (29%, 15% and 32% respectively). In the A2780 model, activity of JNJ-26481585 was superior to that of five other HDAC inhibitors tested. This class leading activity was observed at MTD and optimal route of administration of all compounds and importantly, we also observed significant activity of JNJ-26481585 at concentrations as low as 12.5% of MTD (T/C = 35%). Both class leading activity and significant tumor growth inhibition at concentrations substantially below MTD was also observed in A549, DU145 and HCT116 tumor xenografts. Furthermore, in HCT116, in line with taxotere in prostate models, JNJ-26481585 was shown to be more effective than the SOC, 5-FU. The HCT116 model was used further to address the potential of the compound for clinical utility by exploring alternative dosing schedules to that of QD IP dosing. 3 days on/4 days off, 1 week on/ 1 week off, Q2D and Q7D were all investigated alongside QD dosing and observed to inhibit tumor growth in all cases; Q7D was the only alternative schedule not to achieve efficacy equivalent to that with QD dosing. Finally, data indicating greater activity or equivalence with the SOC suggested that JNJ-26481585 could be used in those indications, thus potency was investigated in drug resistant patient material. In both taxol resistant NSCLC and doxorubicin resistant breast cancer cultures, JNJ-26481585 dramatically inhibited proliferation. We conclude that in preclinical models, JNJ-26481585 was effective at reducing the tumor size to the greatest extent of all HDAC agents studied. Potent antitumoral activity was also observed at doses substantially below MTD and from alternative dosing schedules, suggesting that this could be a promising agent for clinical development in such indications. JNJ-26481585 is currently in Phase I clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5441.