Abstract B042: Clinical development and mechanism of action of LRK-4189, a first-in-class degrader of the lipid kinase PIP4K2C

Abstract

Cancer cells maintain their fitness by developing survival adaptations that foster escape from intrinsic and extrinsic mechanisms of cell death in conditions of stress. Phosphatidylinositol 5-phosphate 4-kinase, type II, gamma (PIP4K2C) is a lipid kinase associated with poor outcomes in multiple tumors including colorectal cancer (CRC), pancreatic, and breast cancer (Llorente et. al). PIP4K2C regulates local pools of PI(4,5)P2 through a catalytic-independent mechanism and is co-opted by cancer cells to increase their fitness by adapting to metabolic stress and evading immune surveillance. (Wang et al.). We have developed LRK-4189, an orally bioavailable, selective degrader of PIP4K2C with sub- nanomolar potency in primary human cells. LRK-4189-mediated degradation of PIP4K2C leads to intrinsic cell death and upregulation of the STAT1 pathway and signaling in microsatellite stable colorectal cancer (MSS CRC) cells. Treatment of human primary spheroids derived from tumor resections of MSS-CRC patients leads to increased tumor killing and down-modulation of key oncogenic transcriptional pathways. In a recent Phase 1 study in healthy volunteers, LRK-4189 demonstrated safety and tolerability as well as positive proof-of-mechanism with profound degradation of PIP4K2C in peripheral PBMC following a single oral dose. Degradation of PIP4K2C in tumors leads to modulation of key pro-tumorigenic pathways and upregulation of cytokines, chemokines, and stress-associated receptors. Emerging data from primary patient samples informing both translation and mechanism of action will be discussed. In addition, new in vivo data supporting expansion into other cancers will be highlighted. Collectively, our results demonstrate that PIP4K2C is conditionally essential under settings of metabolic stress, where its loss induces immunogenic cell death. Clinical studies with LRK-4189 are ongoing with enrollment of cancer patients planned in 2026. 1. Llorente et. al. Nat. Rev. Cancer 2025 2. Wang DG et al. Cell Rep. 2019 Krista B. Goodman, Eva d'Hennezel, Morgan O'Shea, Guosen Ye, Andrew Good, Melvyn Chow, Julie Arnold, Lilly Ein, Sydney Alnemy, Erica Dube, Mike Perricone, Phillipa Graham, Alice Bexon, Catherine Sabatos-Peyton. Clinical development and mechanism of action of LRK-4189, a first-in-class degrader of the lipid kinase PIP4K2C [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B042.