Abstract 6875: Preclinical development of a novel small molecule multitarget inhibitor LCI133 for endometrial adenocarcinoma
Authors: Qi Zhang, Vaidehi Mujumdar, Ritchie Delara, Krishnaiah Maddeboina, Dhananjaya Pal, Bharath Yada, Hailey Dryden, Wendel Naumann, Yovanni Casablanca, Erin Crane, Jubilee Brown, Cody Mchale, Donald Durden
Journal: Cancer Research (2025)

Abstract Objective: Endometrial cancer (EC) is the most common gynecologic malignancy with rising mortality and limited targeted therapies. LCI133, an in silico-designed triple inhibitor of CDK4/6-CDK9-AURK, has demonstrated nano-molar potency against PTEN-mutant EC cells lines and favorable in vivo tolerability. Genetically engineered mouse model (GEMM) is the optimal approach to investigate cancer therapeutics in an immunocompetent setting. The objective of this study is to: 1) describe the physiochemical and pharmacokinetic properties of LCI133, 2) establish and characterize the Pgr-Cre; Pten fl/fl GEMM of EC, 3) assess the preliminary effect of LCI133 on GEMM disease burden. Methods: 1) LCI133 was profiled for target inhibition by cell-free screen and KinomeSCAN. In vivo PK/ADME properties were assessed as described by Veena Bala.5 In vitro potency was assessed by IC50 assay, cell cycle assay, qRT-PCR and immunoblotting at the indicated timepoints for target biomarkers. 2) Pgr-Cre;Ptenfl/fl mice with conditional PTEN deletion were generated by crossbreeding PTEN floxed mice (Ptenflox)with mice expressing Cre under the regulation of the progesterone receptor promoter (PgRCre). Alterations of PTEN/PI3K/AKT pathway were validated by qRT-PCR and immunoblotting. Histopathologic features of female reproductive tract (FRT) were characterized by H&amp;E and immunohistochemistry staining. FRT relative size was normalized to mouse body mass. 3) Beginning at 4-5 weeks of age, formulated LCI133-HCl was administered to Pgr-Cre;Ptenfl/fl mice intraperitoneally daily for 21 days. Animal weight was recorded during treatment. Relative FRT size, pathology and target inhibition were assessed at endpoint. Results: 1) LCI133 demonstrates favorable preclinical PK/ADME profile. LCI-HCl salt form is superior to free form. 2) We confirmed loss of PTEN in Pgr-Cre;Ptenfl/fl FRT with concomitant increases in pAKT. Endometrial adenocarcinoma with serosal and lympho-vascular invasion in a background of hyperplasia was identified at 7-8 weeks of age with high penetrance. Conditional loss of PTEN correlates with expression of Pgr, predominantly in the endometrium and myometrium. 3) LCI133 treatment was associated with decreased relative FRT size, reduced angiogenesis and target suppression. Conclusion: In silico-designed LCI133, as a highly selective inhibitor against CDK4/6-CDK9-AURK with nano-molar potency and favorable PK/ADME properties, demonstrated promising in vivo therapeutic index in immunocompetent mouse models. Citation Format: Qi Zhang, Vaidehi Mujumdar, Ritchie Delara, Krishnaiah Maddeboina, Dhananjaya Pal, Bharath Yada, Hailey Dryden, Wendel Naumann, Yovanni Casablanca, Erin Crane, Jubilee Brown, Cody Mchale, Donald Durden. Preclinical development of a novel small molecule multitarget inhibitor LCI133 for endometrial adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6875.