Abstract PR011: A first-in-class Pin1 degrader provides robust PKPD response and efficacy in PDAC models
TL;DR
A highly selective, first-in-class Pin1 degrader is developed which demonstrated robust PKPD in vivo with sustained target engagement observed following a single dose and it is demonstrated that Pin1 degraders drive significant tumor growth inhibition (TGI) across multiple PDAC efficacy models.
Abstract
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.