In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2787-2787
Abstract:
PI3 Kinase and mTOR have been identified as promising targets for the treatment of cancer. These enzymes participate in related, but not redundant, signaling networks to transmit cellular growth and survival signals, which are hallmarks of tumor growth. An interest in targeting both of these two important points along this critical signaling pathway, and the ability to leverage the high degree of structural similarity in the active sites of PI3K and mTOR kinase, has resulted in the discovery of GDC-0980 as a Class I PI3K and mTOR kinase inhibitor for oncology indications. The structure, efficacy, and medicinal chemistry behind the discovery of this compound is described. Beginning with the morpholin-4-yl-thieno[3,2-d]pyrimidine core of the Class I PI3K inhibitor GDC-0941, structural substitutions were made external to the core that added mTOR potency, improved the metabolic stability in vitro and in vivo, and lowered the plasma protein binding of the scaffold. Homology models of mTOR using PI3Kγ structures with bound inhibitors provided hypotheses for increasing mTOR potency relative to previous compounds. The solubility of the modified compounds was improved through the addition of polar functionality in the solvent exposed region of the scaffold, resulting in GDC-0980. GDC-0980 is potent across Class I isoforms with IC50's of 5, 27, 7, and 14 nM for PI3Kα, β, Δ, and γ, and inhibits mTOR with a Ki of 17 nM. The compound is highly selective versus a large panel of kinases including others in the PIK family. Based on the excellent PK profile, linear increase in exposure, strong potency in a broad range of cancer cells, and high free fraction, GDC-0980 is efficacious in animal models of cancer when dosed orally at low doses. Furthermore, this compound is efficacious when dosed intermittently as well as on a daily schedule. These preclinical data provide compelling support for GDC-0980 as a clinical candidate, and early stage clinical trials are underway. 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 2787. doi:10.1158/1538-7445.AM 2011-2787
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-2787
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
