Abstract 2249: Development and validation of a pharmacodynamic (PD) assay for TOS-358, the first covalent inhibitor of PI3Kα in clinical development

Abstract

Abstract TOS-358 is a first-in-class covalent inhibitor of PI3Kα and is currently in clinical development in a variety of solid malignancies. We have developed a fit-for-purpose pharmacodynamic assay to evaluate the target occupancy of TOS-358 in in vitro and in vivo setting at multiple timepoints. The PI3Kα assay allows direct measurement of both occupied and total protein in multiple different samples and tissue types. Signals of occupied and unoccupied PI3Kα proteins can be readily measured in cellular and in vivo samples. The assay was utilized in a large panel of cancer cell lines, revealing a direct correlation between target occupancy and pathway inhibition of markers such as phosphoAKT and phosphoS6. Critically, these correlations revealed the need to achieve near complete suppression of PI3Kα to enable sustained pathway inhibition and cancer cell death. We furthermore utilized this assay to explore the turnover rate of PI3Kα across multiple diverse tumor types, mutations, and tissues. This approach enables highly sensitive target engagement analysis of TOS-358 across multiple formats. Citation Format: John R. MacDougall, Raymond Mak, John Bradley, Allison Simpson, Claire May, Lan Wei, Kendra Ouellette, Marty Olbrot, Jimmy Blair, Neil Dhawan, Wei Chen. Development and validation of a pharmacodynamic (PD) assay for TOS-358, the first covalent inhibitor of PI3Kα in clinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2249.