A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction-Reference-Cited by-同舟云学术

A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction

Published:2024-07-05 Issue:6704 Volume:385 Page:91-99
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Ting Pamela Y.¹^ORCID,Borikar Sneha¹^ORCID,Kerrigan John Ryan¹,Thomsen Noel M.¹,Aghania Eamon¹^ORCID,Hinman Amelia E.¹,Reyes Alejandro²^ORCID,Pizzato Nicolas²^ORCID,Fodor Barna D.²^ORCID,Wu Fabian²,Belew Muluken S.¹,Mao Xiaohong¹,Wang Jian¹^ORCID,Chitnis Shripad¹,Niu Wei¹,Hachey Amanda¹,Cobb Jennifer S.¹^ORCID,Savage Nikolas A.¹^ORCID,Burke Ashley¹,Paulk Joshiawa¹^ORCID,Dovala Dustin³,Lin James³,Clifton Matthew C.³^ORCID,Ornelas Elizabeth³^ORCID,Ma Xiaolei³^ORCID,Ware Nathaniel F.¹^ORCID,Sanchez Carina C.¹^ORCID,Taraszka John¹,Terranova Remi²^ORCID,Knehr Judith²^ORCID,Altorfer Marc²^ORCID,Barnes S. Whitney⁴^ORCID,Beckwith Rohan E. J.¹^ORCID,Solomon Jonathan M.¹^ORCID,Dales Natalie A.¹,Patterson Andrew W.¹,Wagner Jürgen²^ORCID,Bouwmeester Tewis²^ORCID,Dranoff Glenn¹,Stevenson Susan C.¹,Bradner James E.¹^ORCID

Affiliation:

1. Novartis Biomedical Research, Cambridge, MA, USA.

2. Novartis Biomedical Research, Basel, Switzerland.

3. Novartis Biomedical Research, Emeryville, CA, USA.

4. Novartis Biomedical Research, San Diego, CA, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.adk6129

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