Abstract 3356: Comparative analysis of approved and undertrial SERDs in estrogen receptor-α (ERα): An in-silico approach
Authors: Unadkat Vishal , Rohit Shishir , Purohit Parva , Mehta Chirag , Goswami Vishal , Barmade Mahesh , Sinha Sonam , Sangle Ganesh 
Published: June 2022

Background: Despite recent advancements in early detection and treatment, breast cancer is the second most common cancer affecting women globally, with 11.7% of total new cases. The disease is the fifth leading cause of cancer mortality worldwide, with 685,000 deaths in 2020. Approximately 75% of all breast cancer are ERα positive and resistant to current therapies like aromatase Inhibitors (AIs) and selective receptors modulators (SERMs). The selective estrogen receptor degrader (SERDs) ability to antagonize and degrade ERα makes them promising therapeutic agents for hormone-refractory breast cancer treatment. Fulvestrant is the only SERD with steroidal core currently approved for ER-positive breast cancer treatment. However, its poor physicochemical properties limit its efficacy. Many non-steroidal SERDs such as Amcenestrant, Elacestrant, Camizestrant, Giredestrant, and LSZ102 are under various advanced development stages. However, their long-term efficacy is yet to be established. Our in- silico studies aim to evaluate and compare multiple SERDs (approved and under trial) in terms of their shape similarity, binding mechanism, and stability with ERα receptor.

Methods: Present work focuses on evaluating and comparing the shape similarity and electrostatic potential of various SERDs with respect to ERα endogenous ligand; estradiol (E2). Docking studies were performed to understand the binding mode of selected SERDs within the active site of ERα. Additional parameters like root-mean square-square deviation (RMSD), root-mean square-fluctuation (RMSF), pocket volume fluctuations, and protein-ligand binding energy were calculated using Molecular Dynamics (MD) simulation techniques to understand the stability and binding mechanism of various SERDs.

Result: Among various evaluated SERDs, Fulvestrant shares the highest whereas Elacestrant shares the lowest shape similarity with E2. All docked SERDs cores occupy the same binding pocket and tend to bind in a similar fashion as E2, with their tail protruding towards helix 12 (H12). As observed interactions with H12 are mainly responsible for ERα downregulation. However, in MD studies analysis, it was found that non-steroidal core molecules were less stable and showed more fluctuations (within active site) than steroidal core molecule (Fulvestrant). Moreover, protein-ligand binding energy for Fulvestrant was found to be lower which corresponds to its higher stability with ERα.

Conclusion: The current study helps us to understand the binding mechanism, antagonism, and downregulation of multiple SERDs, among which Fulvestrant showed the highest binding affinity towards ERα (due to its highest shape similarity with E2) and can interact with and disrupt H12 (due to its long tail) which is a critical component of SERD. This knowledge could further be used to develop novel SERDs for ESR1 mutant and HR-positive breast cancer treatment.

Citation Format: Vishal Unadkat, Shishir Rohit, Parva Purohit, Chirag Mehta, Vishal Goswami, Mahesh Barmade, Sonam Sinha, Ganesh Sangle. Comparative analysis of approved and undertrial SERDs in estrogen receptor-α (ERα): An in-silico approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3356.