Identification of Novel Dual-Target Estrogen Receptor α Degraders with Tubulin Inhibitory Activity for the Treatment of Endocrine-Resistant Breast Cancer

Abstract

Endocrine resistance remains a significant problem in the clinical treatment of estrogen receptor α-positive (ERα + ) breast cancer (BC). In this study, we developed a series of novel dual-functional ERα degraders based on a bridged bicyclic scaffold with selenocyano (SeCN) side chains. These compounds displayed potent ERα degradation and tubulin depolymerization activity. Among them, compounds 35s and 35t exhibited the most promising antiproliferative and ERα degradation activity in multiple ERα + BC cell lines bearing either wild-type or mutant ERα. Meanwhile, compounds 35s and 35t disrupted the microtubule network by restraining tubulin polymerization, evidenced by 35t inducing cell cycle arrest in the G2/M phase. In MCF-7 and LCC2 xenograft models, compounds 35s and 35t remarkably suppressed tumor growth without noticeable poisonousness. Finally, this study provided guidance for developing new dual-target antitumor drug candidates for the ERα + BC therapy, especially for the resistant variant.

Synthesis of Selenocyanated Indoles via PhICl2‐Induced Electrophilic Intramolecular Cyclization of 2‐Alkynylanilines or 2‐Alkenylanilines

“…For instances, p ‐XSC ( I ) was detected to display activity in inhibiting the viability of prostate cancer cells [4b] . Selenocyanate derivative II was reported to exhibit the promising antiproliferative activity in treating breast cancer, [7] while selenocyanatoisoxazole III and diselane IV were proved to be potent antileishmanial agents [8] . Especially, 3‐ selenocyanate substituted indole ( V ) was found to be an antifungal agent for the treatment of superficial and mucocutaneous infections (Figure 1).…”

Discovery of Novel ERα and Aromatase Dual-Targeting PROTAC Degraders to Overcome Endocrine-Resistant Breast Cancer

“…Simultaneously, the decline in estrogen biosynthesis could counteract SERMs’ agonistic effects on tissues like the uterus . Certain dual-targeting inhibitors ( 6 – 8 ) have been identified for the prevention of estrogen production or the inhibition of ER signal transduction in BC. − Although ERα/ARO dual-targeting drugs have not yet entered clinical trials, these studies have demonstrated the fundamental structural characteristics of ERα/ARO dual-targeting candidates, revealing that multitarget compounds may be feasible therapies for treating estrogen receptor-positive (ER + ) BC. Conversely, Ful stands as the initial FDA-approved SERD to exhibit clinical advantages in the management of patients dealing with advanced or metastatic ERα + BC.…”

Ring‐Contracted Artemisinin Derivatives as Novel CDK 4/6 Inhibitors: Synthesis and Anti‐Breast Cancer Evaluation

“…Ribociclib and Palbociclib (Figure 3), two typical selective CDK4/6 inhibitors, have been used for the clinical treatment of estrogen receptorpositive (ER + ) advanced breast cancer. [18] These drugs can directly occupy the kinase ATP-binding site, and lead to the loss of catalytic activity of the cyclin D-CDK4/6 complex in a competitive manner, triggering G 1 phase arrest in tumor cells. However, owing to clinical limitations such as low efficacy, narrow anti-tumor spectrum and acquired drug resistance when used as mono-therapy, [19] they can only be used in combination.…”