Abstract DDT02-01: Discovery of GDC-0032: A beta-sparing PI3K inhibitor active against PIK3CA mutant tumors.
Authors: Olivero Alan G. , Heffron Timothy P. , Baumgardner Matthew , Belvin Marcia , Ross Leanne Berry , Blaquiere Nicole , Bradley Erin , Castanedo Georgette , Derynck Mika , Do Steven , Dotson Jennafer , Dudley Danette , Edgar Kyle , Folkes Adrian , Francis Ross , Gianetti Tony , Goldsmith Richard , Goldsmith Paul , Guan Jane , Harrison Trevor , Heald Robert , Hsu Jerry , Jackson Phillip , Jones Graham , Kim Amy , Kolesnikov Aleks , Lackner Mark , Lee Leslie , Lesnick John , Lewis Cristina , Mamounas Michael , McLean Neville , Murray Jeremy , Ndubaku Chudi , Nonomiya Jim , Pang Jodie , Pegg Neil , Prior Wei Wei , Salphati Laurent , Sampath Deepack , Sideris Stephen , Siu Michael , Staben Steven , Sutherlin Daniel , Ultsch Mark , Wallin Jeff , Wang Lan , Wiesmann Christian , Zhang Xiaolin , Friedman Lori S. 
Published: August 2014

Modifications of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway are frequent in cancer due to multiple mechanisms, including activating mutations of the alpha isoform of PI3K. The dysregulation of this pathway has been implicated in many processes involved in oncogenesis. Thus, PI3K is a promising therapeutic target for cancer. Previously we have disclosed GDC-0941, a class 1 selective PI3K inhibitor and our class 1 PI3K/mTOR kinase inhibitor, GDC-0980. In this presentation we describe the design and discovery of a new class of PI3K inhibitors, which selectively inhibit the activated PI3Kα isoform relative to the PI3Kβ isoform.

A lead was identified from a high throughput screen (HTS) that resulted in a novel chemical series of kinase inhibitors. Through a structure-based approach, this lead was optimized to provide very potent inhibitors of PI3K. In addition, this chemical series allowed for designing molecules that have different selectivity patterns with respect to the class 1 PI3K isoforms. In particular, a series of inhibitors were designed that could preferentially inhibit PI3Kα relative to PI3Kβ (“beta-sparing”). Further modification of the physicochemical properties led to the discovery of GDC-0032.

GDC-0032 is a potent inhibitor of PI3Kα (PIK3CA) isoform with a Ki =0.2 nM, and with reduced inhibitory activity against PI3Kβ. This selectivity profile allowed for greater efficacy in vivo at the maximum tolerated dose relative to a pan inhibitor in representative PI3Kα (PIK3CA) mutant xenografts. It is notable that GDC-0032 preferentially inhibited PI3Kα (PIK3CA) mutant cells relative to cells with wild-type PI3K.

Taken together, GDC-0032 is a potent and effective beta-sparing PI3K inhibitor, which currently is in clinical trials.

Citation Format: Alan G. Olivero, Timothy P. Heffron, Matthew Baumgardner, Marcia Belvin, Leanne Berry Ross, Nicole Blaquiere, Erin Bradley, Georgette Castanedo, Mika Derynck, Steven Do, Jennafer Dotson, Danette Dudley, Kyle Edgar, Adrian Folkes, Ross Francis, Tony Gianetti, Richard Goldsmith, Paul Goldsmith, Jane Guan, Trevor Harrison, Robert Heald, Jerry Hsu, Phillip Jackson, Graham Jones, Amy Kim, Aleks Kolesnikov, Mark Lackner, Leslie Lee, John Lesnick, Cristina Lewis, Michael Mamounas, Neville McLean, Jeremy Murray, Chudi Ndubaku, Jim Nonomiya, Jodie Pang, Neil Pegg, Wei Wei Prior, Laurent Salphati, Deepack Sampath, Stephen Sideris, Michael Siu, Steven Staben, Daniel Sutherlin, Mark Ultsch, Jeff Wallin, Lan Wang, Christian Wiesmann, Xiaolin Zhang, Lori S. Friedman. Discovery of GDC-0032: A beta-sparing PI3K inhibitor active against PIK3CA mutant tumors. [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 DDT02-01. doi:10.1158/1538-7445.AM2013-DDT02-01