Abstract 1616: Preclinical characterization of KSHN001126, a novel, differentiated and steroidal oral selective estrogen receptor degrader (SERD)
Authors: Purohit Parva , Pandya Heta , Unadkat Vishal , Variya Ketan , Sinha Sonam , Barmade Mahesh , Rohit Shishir , Sangle Ganesh 
Published: April 2023

Fulvestrant (FLV) (Faslodex®) is the only clinically approved steroidal SERD that requires painful intramuscular administration. Several oral SERDs are being developed using non-steroidal pharmacophores with the goal of improving efficacy while reducing toxicities. Recently, two advanced non-steroidal oral SERDs failed to meet the primary endpoint of longer progression-free survival. Whereas Elacestrant demonstrated efficacy only in a subset of the population (ESR1 mutant) with poor gastrointestinal tolerability. KSHN001126 was developed as a steroidal SERD by exploring multiple ER-protein conformations and identifying a subpocket around the core hydrophobic site where the molecule can be extended. KSHN001126 perfectly occupies both the original and subpocket formed by the pocket breathing phenomenon. Being steroidal SERD, KSHN001126 has the potential to be efficacious in the mutant/non-mutant conditions. KSHN001126 was studied in MCF-7 cells in- vitro to understand ER localization confirming cytosolic abundance and ERα immobilization. Furthermore, ERα protein quantification using a simple western revealed dose-dependent degradation following KSHN001126 treatment. The MCF-7 xenograft study was performed in nude mice to evaluate antitumor activity of KSHN001126 (10, 30, and 60 mg/kg) administered for 28 days revealing dose-dependent efficacy and ER degradation. Furthermore, KSHN001126 demonstrated dose-dependent reduction in tumor volume in ESR1 Y537S patient derived xenograft (PDX - ST2177), confirming activity against the ESR1 mutation. Following that, the combination of KSHN001126 with Palbociclib or Alpelisib was tested in an MCF-7 xenograft model, as these molecules are clinically approved in combination with SERD. Furthermore, KSHN001126 was evaluated in combination with FLV to assess any potential mechanistic synergy. When KSHN001126 was combined with Palbociclib, Alpelisib, or FLV, significant tumor regression was observed compared to standalone treatment (p0.05 or 0.01). KSHN001126 is currently being tested in additional PDX models. Overall, KSHN001126 demonstrated dose-dependent efficacy (wild type and ESR1 mutation), confirming target engagement and mechanistic synergy (CDK4/6-Palbociclib and PI3K-Alpelisib). Furthermore, KSHN001126 demonstrated additive antitumor efficacy when combined with FLV, indicating a potential additional mechanism other than SERD.

Citation Format: Parva Purohit, Heta Pandya, Vishal Unadkat, Ketan Variya, Sonam Sinha, Mahesh Barmade, Shishir Rohit, Ganesh Sangle. Preclinical characterization of KSHN001126, a novel, differentiated and steroidal oral selective estrogen receptor degrader (SERD) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1616.