Ting, Pamela, Borikar, Sneha, Kerrigan, John, Thomsen, Noel, Aghania, Eamon, Hinman, Amie, Pizzato, Nicolas, Reyes Quiroz, Alejandro, Fodor, Barna, Wu, Fabian, Belew, Muluken, Mao, Xiaohong, Wang, Jian, Chitnis, Shripad, Niu, Wei, Hachey, Amanda, Cobb, Jennifer, Savage, Nik, Burke, Ashley, Paulk, Josh, Dovala, Dustin, Lin, James, Clifton, Matt, Ornelas, Elizabeth, Ma, Xiaolei, Ware, Nate, Sanchez, Carina, Taraszka, John, Terranova, Remi, Knehr, Judith, Altorfer, Marc, Barnes, Whitney, Beckwith, Rohan, Solomon, Jonathan, Dales, Natalie, Patterson, Andrew, Wagner, Juergen, Bouwmeester, Antonius, Dranoff, Glenn, Stevenson, Susan and Bradner, James (2024) A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction. Science (New York, N.Y.), 385 (6704). pp. 91-99. ISSN 1095-9203

Abstract

Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate disease complications and has been intently pursued. However, safe and effective small-molecule inducers of HbF remain elusive. We report the discovery of dWIZ-1 and dWIZ-2, molecular glue degraders of the WIZ transcription factor that robustly induce HbF in erythroblasts. Phenotypic screening of a cereblon (CRBN)-biased chemical library revealed WIZ as a previously unknown repressor of HbF. WIZ degradation is mediated by recruitment of WIZ(ZF7) to CRBN by dWIZ-1, as resolved by crystallography of the ternary complex. Pharmacological degradation of WIZ was well tolerated and induced HbF in humanized mice and cynomolgus monkeys. These findings establish WIZ degradation as a globally accessible therapeutic strategy for SCD.

Item Type:	Article
Keywords:	Animals Humans Mice Adaptor Proteins, Signal Transducing Anemia, Sickle Cell Antisickling Agents Crystallography, X-Ray Drug Discovery Fetal Hemoglobin Kruppel-Like Transcription Factors Macaca fascicularis Nerve Tissue Proteins Proteolysis Small Molecule Libraries Ubiquitin-Protein Ligases
Date Deposited:	13 Aug 2024 00:45
Last Modified:	13 Aug 2024 00:45
URI:	https://oak.novartis.com/id/eprint/52018