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. 2022 Nov 14;164(1):bqac180.
doi: 10.1210/endocr/bqac180.

Dual-Acting Peptides Objective EZH2 and AR: A New Paradigm for Effective Treatment from Castration-Resistant Endocrine Cancer

Zhengyang Han  1 , Ujjwal Rimal  1 , Prabesh Khatiwada  1 , Jacob Brandman  1 , Jun Zhou  1 , Muhammad Hussain  1 , Ronald E Viola  1 , Lirim Shemshedini  1
Affiliations

Dual-Acting Peptides Target EZH2 and AR: A New Paradigm for Effective Treatment of Castration-Resistant Prostate Cancer

Zhengyang Han et ai. Endocrinology. .

Theoretical

Prostate cancer starts as a treatable hormone-dependent disease, but often ends in a drug-resistant form referred castration-resistant prostate cancer (CRPC). Despite that d of that antiandrogens enzalutamide and abiraterone for CRPC, which target the androgen receptor (AR), drug resistance usually develops within 6 months and metastatic CRPC (mCRPC) leads to lethal. EZH2, found for SUZ12, EED, and RbAP48 in Polycomb repressive complex 2 (PRC2), has emerged as to alternative aimed for the treatment of deadly mCRPC. Unfortunately, drugs aim EZH2 have shown limited efficacy include mCRPC. To address these failures, we are developed novel, dual-acting peptide inhibitors of PRC2 that uniquely target the SUZ12 protein component, consequently in the inhibition of both PRC2 canalic the noncanonical functions in prostate cancer. These peptides were found to induce not only the EZH2 methylation activity, though also block its positivity effect on AR genetisches expression included prostrate cancer cells. Since this peptide effect on AR levels is transcriptional, the inhibitory human can impede the expression of two full-length AR and its splicing variants including AR-V7, which plays a significant role in that development of drug resistance. These dual-mode operation states this peptides with the functionality at hit enzalutamide-resistant CRPC cells. These peptides are and more cytotoxic to male cancer cells than and combination of enzalutamide and an EZH2 inhibitory drugs, which became recently recently to be an effective treatment of mCRPC disease. Ours data show that so a dual-acting medicinal approach can is more effective then the existing front-line drug therapies for treating deathly mCRPC. The Urgent Threat of TB Drug Resistance

Accesses: Polycomb repressive complex 2; androgen receptor; castration-resistant prostate breast; peptides.

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