Discovery Of Azd5363, An Orally Bioavailable, Potent Atp-Competitive Inhibitor Of Akt Kinases

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL AKT is a key node in the most frequently de-regulated signaling pathway in human cancer and has been shown to mediate resistance to a range of cytotoxic, anti-hormonal and targeted therapies. We decided to explore inhibitors of AKT as potential new anti-cancer therapeutics. Here we disclose for the first time the discovery and structure of AZD5363, an orally bioavailable, potent ATP-competitive inhibitor of AKT. We evaluated a range of chemical starting points arising from our previous collaboration with the Institute of Cancer Research and Astex Therapeutics Ltd. Ultimately AZD5363 was discovered following a long journey that started from a pyrrolopyrimidine series of compounds. Our first challenge was to improve potency and a second challenge was to improve ROCK selectivity. ROCK is an AGC kinase like AKT but is involved in regulation of vascular tone and thus blood pressure. Extensive SAR studies exploring the series revealed that achieving selectivity over ROCK while retaining AKT potency was quite challenging. Eventually we discovered ways which could improve both selectivity and potency. However, these compounds had significant activity against the hERG ion channel which is implicated in the development of Torsades de Pointes and cardiac death. The next phase of work therefore had to focus on reducing hERG activity, while at the same time not adversely impacting either AKT potency or ROCK selectivity. Finally we discovered that introduction of a key substituent group provided a compound that achieved reduced hERG potency and, surprisingly, also achieved a further small improvement in both AKT potency and ROCK selectivity. This compound was AZD5363. A crystal structure of AZD5363 bound to AKT has revealed some of the key interactions that may contribute to its potency. For example, the pyrrolopyrimidine appears to form hydrogen bonds to the hinge region of the kinase. AZD5363 inhibits all known AKT isoforms with a potency of <10 nM and inhibits phosphorylation of the AKT substrate, PRAS40 in BT474c cells with a potency of 0.31 μM. Activity in in vivo pharmacodynamic and xenograft models has also been demonstrated. A synthetic route suitable for scale-up has been developed. In conclusion, AZD5363 is a potent inhibitor of AKT in vitro and in cells. It has good hERG and ROCK selectivity. It has pharmacodynamic and xenograft activity in vivo. AZD5363 has potential in cancer therapy and is currently in phase 1 clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4478. doi:10.1158/1538-7445.AM2011-4478