Kerrigan, Ryan, Thomsen, Noel, Cernijenko, Artiom, Kochanek, Sarah, Dewhurst, Janetta, O'Brien, Gary, Ware, Nate, Manning, James, Ornelas, Elizabeth, Savage, Nik, Patterson, Andrew, Bonazzi, Simone, Borikar, Sneha, Ting, Pamela, Ma, Xiaolei, Lam, Philip and Dales, Natalie (2024) Discovery and Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin In-duction to Treat Sickle Cell Disease. Journal of medicinal chemistry, 67 (22). pp. 20682-20694. ISSN 0022-2623

Abstract

Sickle cell disease (SCD) is a prevalent, life-threatening condition with few treatment options, attributed to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) with small molecules has been pursued as a treatment to ameliorate many disease complications, but with limited success. Herein we report the discovery of 10, a novel, potent and selective molecular glue degrader of the transcription factor WIZ that robustly induces HbF expression as a potential treatment for SCD. 10 was optimized from a phenotypic screening hit utilizing insights from x-ray crystallography and computational modeling to improve potency, selectivity and in vivo exposure. In an hNBSGW mouse xenograft model, 10 demonstrated robust WIZ degradation and HbF induction, superior to the standard-of-care.

Item Type:	Article
Keywords:	WIZ degrader
Date Deposited:	18 Jan 2025 00:45
Last Modified:	18 Jan 2025 00:45
URI:	https://oak.novartis.com/id/eprint/54660