Abstract B078: The novel small molecule inhibitor LLS132 reduces pancreatic cancer growth, in part, through modulation of the cell cycle pathway

Abstract Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive cancer with a 5-year survival rate of approximately 13% in the United States, highlighting the urgent need for effective, clinically translatable therapies beyond those currently offering limited benefit. To address this, we developed a novel small-molecule inhibitor, LLS132, and evaluated its safety and efficacy in multiple preclinical models of PDA. We assessed the antiproliferative activity of LLS132 in vitro using human pancreatic cancer cell lines and organoids derived from the genetically engineered LSL-Kras G12D, LSL-Trp53 R172H/+, Pdx1-Cre (KPC) mouse model. In vivo efficacy and safety were evaluated using subcutaneous and orthotopic pancreatic allograft models, as well as KPC mice. Pharmacokinetics and tumor penetration were analyzed by LC-MS, while RNA sequencing and western blotting were used to identify molecular pathways affected by LLS132. LLS132 inhibited the growth of human pancreatic cancer cell lines and KPC-derived tumor organoids in vitro. In vivo, LLS132 significantly suppressed tumor growth across all tested models. In a subcutaneous allograft model, LLS132 (30 mg/kg, i. p. , 5x/week for 1 week) reduced tumor burden by 79% compared to controls, outperforming gemcitabine (100 mg/kg, i. p. , 2x/week), which achieved 48% inhibition. In an orthotopic model, LLS132 at 37. 5 mg/kg (75% of the maximum tolerated dose, i. p. , 5x/week) reduced tumor volume by 43% after 3 weeks and in the clinically relevant KPC model, LLS132 suppressed tumor progression by 65% over 30 days. Importantly, treatment was well tolerated, with no significant weight loss or liver toxicity observed. Pharmacokinetic analysis revealed a maximum plasma concentration of 19063. 7 ± 6656. 4 ng/mL at tmax = 1. 3± 0. 5 hours, and a tumor concentration of 111. 5 ± 22. 5 ng/mg in KPC mice, confirming effective tumor penetration. Transcriptomic analysis of LLS132-treated Panc-1 cells identified cell cycle regulation as a key pathway, with CDK2 emerging as an important target. LLS132 reduced CDK2 expression in both cancer cells and allograft tumor tissue. In conclusion, LLS132 is a promising therapeutic candidate for PDA, exhibiting potent antitumor activity and favorable safety in preclinical models, mediated in part through suppression of CDK2 and modulation of cell cycle pathways. Citation Format: Irena Krga, Laura Musumeci, Hala Addassi, Kit S. Lam, Ruiwu Liu, Gerardo G. Mackenzie. The novel small molecule inhibitor LLS132 reduces pancreatic cancer growth, in part, through modulation of the cell cycle pathway abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr B078.