Prostate cancer affects 1 in 6 men and is the second most common cause of cancer-related death. Since the majority of prostate cancers critically depend on androgens for growth, androgen deprivation therapy is a frontline treatment for advanced prostate cancer. The majority of prostate tumors initially respond to androgen deprivation therapy, but eventually the disease often progresses to castration-resistant prostate cancer. However, the current therapies that only reduce androgen produced in the testis do not affect androgen produced by adrenal glands can also produce androgens. This extra-testicular androgen production is thought to be a key factor in the development of castration resistant prostate cancer. CYP17 is a P450 enzyme that catalyzes the last step of androgen biosynthesis in both the testis and the adrenals. Inhibition of CYP17 therefore completely blocks androgen production and it is thus thought to be more effective to prevent prostate cancer progression than current therapies. Angion Biomedica has identified a promising series of proprietary non-steroidal CYP17 inhibitors. Our lead compound is potent, orally bioavailable, and significantly reduces serum testosterone levels in mice. Treatment of rats and mice with our lead CYP17 inhibitor significantly reduces the weights of androgen dependent organs. In two mouse xenograft models of androgen-dependent tumor growth our lead CYP17 inhibitor markedly reduces primary tumor growth, serum testosterone and PSA levels. Angion is currently further evaluating the therapeutic potential of this series of compounds as a possible therapy for castration resistant prostate cancer. Citation Format: Bert Oehlen, Siobhan McCormack, Gaifeng Ma, Dong Sung Lim, Bijoy Panicker, Itzhak D. Goldberg. Characterization of a new non-steroidal small molecule inhibitor of CYP17 for castration-resistant prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5560. doi:10.1158/1538-7445.AM2013-5560

Abstract Retinoids, such as the prototypical retinoid all trans retinoic acid (ATRA), have been used successfully in the treatment of acute promyelocytic leukemia (APL) patients. They have also been tested for efficacy in solid tumors, including breast cancer. Despite promising preclinical data, the clinical success of using ATRA for breast cancer patients has been limited so far. We hypothesize that this is largely due to three factors: (1) a lack of understanding of the patient population that is likely to respond to retinoid therapy, (2) a significant induction of retinoic acid metabolism with retinoid therapy, resulting in sub-optimal retinoid exposure in tumors and (3) the narrow therapeutic index of ATRA. Several recent studies indicate that breast cancer cells that express the Retinoic Acid Receptor Alpha (RARA) are more likely to respond to retinoic acid than cells without RARA expression. This provides a rationale for selection of patients that are likely to benefit from retinoid therapy in future clinical trials. The cytochrome P450 enzyme CYP26 is the key enzyme involved in ATRA metabolism. CYP26A1 expression is elevated in breast cancer tissue compared to normal tissue and CYP26A1 expression is negatively correlated with patient survival. Angion has identified orally bioavailable small molecule inhibitors of CYP26. Angion's lead inhibitor blocks retinoid metabolism in tumor cells and enhances serum and tumor retinoic acid levels. The compound shows robust single agent efficacy in several murine breast cancer xenograft models. By elevating endogenous serum and tumor retinoic acid levels in a physiological range, CYP26 inhibition therapy is likely to result in a better therapeutic index than systemic retinoid therapy. The identification of orally bioavailable, potent, and selective CYP26 inhibitors eliminates two major drawbacks of systemic retinoid therapy, and– in combination with new insights in selecting patients that are more likely to respond to retinoid therapy– may provide a new impetus for evaluation of retinoic acid signaling modulators as a treatment for breast cancer patients. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B257. Citation Format: Bert Oehlen, Gaifeng Ma, Siobhan McCormack, Dong Sung Lim, Jim Tarrant, Xiaokang Zhu, Bijoy Panicker, Itzhak D. Goldberg. Identification of new CYP26 inhibitors with efficacy in breast cancer xenograft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B257.

A highly effective one-pot Friedländer quinoline synthesis using inexpensive reagents has been developed. o-Nitroarylcarbaldehydes were reduced to o-aminoarylcarbaldehydes with iron in the presence of catalytic HCl (aq.) and subsequently condensed in situ with aldehydes or ketones to form mono- or di-substituted quinolines in high yields (66-100%).