Christoph Schultes

Toluidinesulfonamide Hypoxia-Induced Factor 1 Inhibitors: Alleviating Drug–Drug Interactions through Use of PubChem Data and Comparative Molecular Field Analysis Guided Synthesis

Inhibitors of hypoxia-inducible factor 1 (HIF-1) represent promising anticancer therapeutics. We have identified a series of potent toluidinesulfonamide HIF-1 inhibitors. However, the series was threatened by a potential liability to inhibit CYP2C9 which could cause dangerous drug-drug interactions when being coadministered with other drugs. We used structure-activity data from the PubChem database to develop a topomer CoMFA model that guided the design of novel sulfonamides with high selectivity for HIF-1 over CYP2C9 inhibition.

Abstract LB-294: Development and characterization of novel orally available hypoxia-inducible factor (HIF) signaling inhibitors as dual-mechanism cancer therapeutics

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The HIF signaling pathway is a crucial way in which tumors can circumvent the constraints of regions of low oxygen (hypoxia) to induce angiogenesis and maintain proliferation. The oxygen regulated subunit of the transcription factor hypoxia-inducible factor 1 (HIF1), HIF1αlpha, is a positive factor in tumor growth and its expression has been correlated with poor patient prognosis in a number of settings. We here present in vitro and in vivo data for a novel series of orally available small-molecule HIF signaling modulators that show nanomolar inhibition of the HIF signaling pathway in addition to potent anti-proliferative activity against a large number of cell lines derived from solid and blood tumors (EC50 in the range 1-100nM). Phenotypically, the compounds elicit an initial G2/M arrest, followed by the induction of caspase-3/7 and the onset of apoptosis. The in vitro results also translate into in vivo animal models. The lead compounds from the series show efficacy in tumor xenograft mouse models, with dose-dependent tumor growth inhibition of 60-70% after oral dosing (MDA-MB-231 xenograft). Structural optimisation has additionally allowed us to improve the PK and physicochemical characteristics of the compounds, with a lead candidate currently in formal pre-clinical development with the aim of entering a Phase 1 clinical trial in multiple myeloma at the end of 2010. In conclusion, we believe that the development towards clinical Proof-of-Concept of this new class of dual-mechanism inhibitors of HIF signaling and cell proliferation presents a promising new option for cancer therapeutics. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 LB-294.