Abstract 841: Therapeutic targeting of cancer cells in the hypoxic microenvironment using an orally bioavailable small molecule inhibitor of carbonic anhydrase IX

Abstract

Abstract Carbonic anhydrase IX (CAIX) is a membrane-bound, hypoxia-inducible enzyme that is highly expressed in many types of solid tumors, is an independent marker of poor prognosis and functions as a critical component of the pH regulatory machinery required by hypoxic cancer cells for survival, invasion and metastasis. These attributes make CAIX an attractive therapeutic target for cancer therapy. The development of pharmacologic inhibitors that selectively target tumor-associated, extracellular carbonic anhydrases (CAs) without “off-target” inhibition of cytosolic isoforms is critical for their use as cancer therapeutics. Here, we characterize an orally bioavailable, highly selective small molecule inhibitor of CAIX and CAXII, SLC-0111, and investigate its efficacy when used as a monotherapy and in combination with conventional chemotherapy in vivo. SLC-0111 exhibited a favorable in vitro ADME profile, including IC50 values of >100 mM against most CYP isoforms, an IC50 for hERG inhibition of >30 mM and absence of mutagenic properties. Incubation of the compound with 67NR cells constitutively expressing human CAIX significantly suppressed, in a dose-dependent fashion, a drop in extracellular pH in a cell-based CAIX activity assay. The active compound was formulated as a self-emulsifying liquid for oral administration in vivo and evaluation of plasma levels showed good oral bioavailability of 40%. Toxicity studies involving repeat dosing by oral gavage for 7 days established maximum-tolerated doses in excess of 1,000 and 750 mg/kg for rats and dogs, respectively. Daily oral administration of SLC-0111 to mice harboring established MDA-MB-231 LM2-4 orthotopic human breast tumors, a model of hypoxic, CAIX-positive triple negative metastatic breast cancer, resulted in a significant, dose-dependent reduction in tumor growth, with 30% inhibition at a dose of 50 mg/kg, no toxicity and a 10-fold therapeutic window. Treatment also reduced viable tumor volume as determined by 18F-deoxyglucose uptake detected by positron emission tomography. Furthermore, treatment of mice with SLC-0111 in combination with paclitaxel resulted in significantly reduced tumor growth compared to either treatment administered alone, with no additional toxicity and plasma levels of SLC-0111 similar to those observed with its use as a monotherapy. Plasma levels of SLC-0111 showed dose proportionality and analysis of tumor levels demonstrated a greater than proportional relationship, with a 4-fold increase in dose (25-100 mg/kg) resulting in more than a 13-fold increase in tumor levels of the compound. Collectively, these data demonstrate the potential utility of SLC-0111 as a safe, target-specific inhibitor of CAIX for the treatment of cancer, particularly in combination with conventional chemotherapy. Citation Format: Paul C. McDonald, Jasbinder Sanghera, Madhu Singh, Yuanmei Lou, Marylou Vallejo, Claudiu T. Supuran, Shoukat Dedhar. Therapeutic targeting of cancer cells in the hypoxic microenvironment using an orally bioavailable small molecule inhibitor of carbonic anhydrase IX. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 841. doi:10.1158/1538-7445.AM2014-841