Gillian M. Lamont

Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor

Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.

Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases.

Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model.

Sulfonyl-morpholino-pyrimidines: SAR and development of a novel class of selective mTOR kinase inhibitor

High throughput screening to identify inhibitors of the mTOR kinase revealed sulfonyl-morpholino-pyrimidine 1 as an attractive start point. The compound displayed good physicochemical properties and selectivity over related kinases such as PI3Kα. Library preparation of related analogs allowed the establishment of additional SAR understanding and in particular the requirement for a key hydrogen bond donor motif at the 4-position of the phenyl ring in compounds such as indole 19. Isosteric replacement of the indole functionality led to the identification of urea compounds such as 32 that show good levels of mTOR inhibition in both enzyme and cellular assays.

Investigation of (E)-3-[4-(2-Oxo-3-aryl-chromen-4-yl)oxyphenyl]acrylic Acids as Oral Selective Estrogen Receptor Down-Regulators

A novel estrogen receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective estrogen receptor down-regulators, which led us to the discovery of potent down-regulating antagonists, such as 33. Subsequent optimization and removal of the 7-hydroxy group led to coumarin 59, which had increased potency and improved rat bioavailability relative to SS5020.

Identification and optimisation of 7-azaindole PAK1 inhibitors with improved potency and kinase selectivity

A novel series of PAK1 inhibitors was discovered from a kinase directed screen. SAR exploration in the selectivity pocket and solvent tail regions was conducted to understand and optimise PAK1 potency and selectivity against targeted kinases. A liganded PAK1 crystal structure was utilised to guide compound design. Permeability and kinase selectivity impacted the translation of enzyme to cellular PAK1 potency. Compound 36 (AZ-PAK-36) demonstrated improved Gini coefficient, good PAK1 cellular potency and has utility as a tool compound for target validation studies.

Synthesis of 3-(hetero)aryl tetrahydropyrazolo[3,4-c]pyridines by Suzuki-Miyaura cross-coupling methodology.

A new synthetic route to 3-(heteroaryl) tetrahydropyrazolo[3,4-c]pyridines has been developed that uses the Suzuki-Miyaura cross-coupling of a triflate 6 with (hetero)aryl boronic acids or esters. Using Pd(OAc)2 and XPhos or an XPhos precatalyst, a diverse range of substituents at the C3 position of the tetrahydropyrazolo[3,4-c]pyridine skeleton were prepared. The use of pivaloyloxymethyl and benzyl protection also offers the potential to differentially functionalize the pyrazole and tetrahydropyridine nitrogens.

Abstract 4478: 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