The prolyl isomerase Pin1 is a critical regulator of protein conformation and is frequently overexpressed across a spectrum of human malignancies. Its enzymatic activity is essential for stabilizing numerous oncogenic client proteins while promoting the turnover of key tumor suppressors, thereby driving neoplastic cell survival, proliferation, and therapeutic resistance. Targeting Pin1 offers a promising therapeutic strategy to address pancreatic ductal adenocarcinoma (PDAC).
We describe the discovery and characterization of a selective heterobifunctional degrader targeting Pin1. We hypothesized that complete protein elimination, rather than enzymatic inhibition alone, would deliver a more profound and durable anti-tumor response. We have developed an in vivo tool molecule, characterized by rapid in vitro degradation kinetics, single-digit nM DC50 activity in rodent cellular systems, and proteome-wide selectivity confirmed by whole-cell proteomics (WCP) across multiple cell lines. We report that this optimized tool has pharmacokinetic characteristics suitable for in vivo studies. In addition, treatment with Pin1 degraders induces deep and sustained degradation of Pin1 in vivo. Finally, we report single agent efficacy in in PDAC in vivo models.
We have developed a highly selective, first-in-class Pin1 degrader which demonstrated robust PKPD in vivo with sustained target engagement observed following a single dose. We also demonstrate that Pin1 degraders drive significant tumor growth inhibition (TGI) across multiple PDAC efficacy models.
Morgan B. O'Shea, Guosen B. Ye, Melvyn B. Chow, Lilly B. Ein, Julie B. Arnold, Jessica Freda, Erica Dube, Pradeep B. Kota, Swanny B. Lamboy-Rodriguez, Scott B. Eron, Catherine B. Sabatos-Peyton, Andrew Good, Eva B. d'Hennezel, Krista Goodman. A first-in-class Pin1 degrader provides robust PKPD response and efficacy in PDAC models [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 B046.
Morgan B. O'Shea, Guosen B. Ye, Melvyn B. Chow et al.· Clinical Cancer Research· 0 citations
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.
Krista Goodman, Eva B. d'Hennezel, Morgan B. O'Shea et al.· Clinical Cancer Research· 0 citations
The prolyl isomerase Pin1 is a critical regulator of protein conformation and is frequently overexpressed across a spectrum of human malignancies. Its enzymatic activity is essential for stabilizing numerous oncogenic client proteins while promoting the turnover of key tumor suppressors, thereby driving neoplastic cell survival, proliferation, and therapeutic resistance. Targeting Pin1 offers a promising therapeutic strategy to address pancreatic ductal adenocarcinoma (PDAC).
We describe the discovery and characterization of a selective heterobifunctional degrader targeting Pin1. We hypothesized that complete protein elimination, rather than enzymatic inhibition alone, would deliver a more profound and durable anti-tumor response. We have developed an in vivo tool molecule, characterized by rapid in vitro degradation kinetics, single-digit nM DC50 activity in rodent cellular systems, and proteome-wide selectivity confirmed by whole-cell proteomics (WCP) across multiple cell lines. We report that this optimized tool has pharmacokinetic characteristics suitable for in vivo studies. In addition, treatment with Pin1 degraders induces deep and sustained degradation of Pin1 in vivo. Finally, we report single agent efficacy in in PDAC in vivo models.
We have developed a highly selective, first-in-class Pin1 degrader which demonstrated robust PKPD in vivo with sustained target engagement observed following a single dose. We also demonstrate that Pin1 degraders drive significant tumor growth inhibition (TGI) across multiple PDAC efficacy models.
Morgan B. O'Shea, Guosen B. Ye, Melvyn B. Chow, Lilly B. Ein, Julie B. Arnold, Jessica Freda, Erica Dube, Pradeep B. Kota, Swanny B. Lamboy-Rodriguez, Scott B. Eron, Catherine B. Sabatos-Peyton, Andrew Good, Eva B. d'Hennezel, Krista Goodman. A first-in-class Pin1 degrader provides robust PKPD response and efficacy in PDAC models [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 PR011.
Morgan B. O'Shea, Guosen B. Ye, Melvyn B. Chow et al.· Clinical Cancer Research· 0 citations
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