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Last update 08 May 2025

WIZ

Last update 08 May 2025

Basic Info

Synonyms

Protein Wiz, Widely-interspaced zinc finger-containing protein, WIZ

+ [3]

Introduction

May link EHMT1 and EHMT2 histone methyltransferases to the CTBP corepressor machinery. May be involved in EHMT1-EHMT2 heterodimer formation and stabilization (By similarity).

Drugs associated with WIZ

BMS-986470

Target

CRBN x WIZ x ZBTB7A

Mechanism

CRBN modulators [+2]

Active Org.

Bristol Myers Squibb Co.

Originator Org.

Bristol Myers Squibb Co.

Active Indication

Anemia, Sickle Cell

Inactive Indication-

Drug Highest PhasePhase 1/2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

GLB-005

Target

WIZ

Mechanism

WIZ modulators

Active Org.

GluBio Therapeutics, Inc.

Originator Org.

GluBio Therapeutics, Inc.

Active Indication

Anemia, Sickle Cell [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

WIZ inhibitors(Novartis)

Target

WIZ

Mechanism

WIZ inhibitors

Active Org.

Novartis Pharmaceuticals Corp.

Originator Org.

Novartis Pharmaceuticals Corp.

Active Indication

Anemia, Sickle Cell

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with WIZ

NCT06481306

/ RecruitingPhase 1/2

A Phase 1/2a, First-in-human, Randomized, Double-blinded, Placebo-controlled, Dose-finding Study in Healthy Volunteers and Participants With Sickle Cell Disease to Evaluate the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics, pH and Food Effect, and Preliminary Efficacy of BMS-986470

The purpose of this study is to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics, pH and food effect, and preliminary efficacy of BMS-986470 in healthy volunteers and participants with sickle cell disease.

Start Date17 Jul 2024

Sponsor / Collaborator

Bristol Myers Squibb Co.

100 Clinical Results associated with WIZ

100 Translational Medicine associated with WIZ

0 Patents (Medical) associated with WIZ

Literatures (Medical) associated with WIZ

28 Nov 2024·Journal of Medicinal Chemistry

Discovery and Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin Induction to Treat Sickle Cell Disease

Article

Author: Manning, James R. ; Savage, Nikolas A. ; Cernijenko, Artiom ; Ware, Nathaniel F. ; Ma, Xiaolei ; Kochanek, Sarah E. ; Lam, Philip ; Borikar, Sneha ; Ting, Pamela Y. ; Patterson, Andrew W. ; Dales, Natalie A. ; Bonazzi, Simone ; Thomsen, Noel M. ; Partridge, James R. ; Dewhurst, Janetta ; Kerrigan, John Ryan ; Hinman, Amelia E. ; Ornelas, Elizabeth ; Sanchez, Carina C. ; O’Brien, Gary

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. These results highlight the potential of WIZ degraders as a promising therapy for sickle cell disease.

05 Jul 2024·Science

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

Article

Author: Barnes, S. Whitney ; Fodor, Barna D. ; Knehr, Judith ; Terranova, Remi ; Burke, Ashley ; Patterson, Andrew W. ; Bradner, James E. ; Altorfer, Marc ; Reyes, Alejandro ; Dranoff, Glenn ; Hinman, Amelia E. ; Paulk, Joshiawa ; Stevenson, Susan C. ; Wang, Jian ; Taraszka, John ; Beckwith, Rohan E. J. ; Ting, Pamela Y. ; Clifton, Matthew C. ; Ma, Xiaolei ; Solomon, Jonathan M. ; Wu, Fabian ; Dovala, Dustin ; Niu, Wei ; Hachey, Amanda ; Ornelas, Elizabeth ; Cobb, Jennifer S. ; Mao, Xiaohong ; Dales, Natalie A. ; Kerrigan, John Ryan ; Lin, James ; Pizzato, Nicolas ; Savage, Nikolas A. ; Thomsen, Noel M. ; Ware, Nathaniel F. ; Aghania, Eamon ; Borikar, Sneha ; Chitnis, Shripad ; Belew, Muluken S. ; Sanchez, Carina C. ; Wagner, Jürgen ; Bouwmeester, Tewis

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.

01 Nov 2023·Plant Communications

Assembly of JAZ–JAZ and JAZ–NINJA complexes in jasmonate signaling

Article

Author: Yao, Jian ; Lam, Vinh Q ; Suino-Powell, Kelly ; Zhang, Yaguang ; Cao, Xiaoman ; Zhang, Feng ; Novick, Scott ; Zhou, Yuxin ; Zhou, X Edward ; Griffin, Patrick R ; Howe, Gregg A ; Zhu, Yuanye ; Kariapper, Leena ; Moreno, Javier ; Melcher, Karsten ; Vanegas-Cano, Leidy ; He, Qing ; Zheng, Jie ; Sugimoto, Koichi

Jasmonates (JAs) are plant hormones with crucial roles in development and stress resilience. They activate MYC transcription factors by mediating the proteolysis of MYC inhibitors called JAZ proteins. In the absence of JA, JAZ proteins bind and inhibit MYC through the assembly of MYC-JAZ-Novel Interactor of JAZ (NINJA)-TPL repressor complexes. However, JAZ and NINJA are predicted to be largely intrinsically unstructured, which has precluded their experimental structure determination. Through a combination of biochemical, mutational, and biophysical analyses and AlphaFold-derived ColabFold modeling, we characterized JAZ-JAZ and JAZ-NINJA interactions and generated models with detailed, high-confidence domain interfaces. We demonstrate that JAZ, NINJA, and MYC interface domains are dynamic in isolation and become stabilized in a stepwise order upon complex assembly. By contrast, most JAZ and NINJA regions outside of the interfaces remain highly dynamic and cannot be modeled in a single conformation. Our data indicate that the small JAZ Zinc finger expressed in Inflorescence Meristem (ZIM) motif mediates JAZ-JAZ and JAZ-NINJA interactions through separate surfaces, and our data further suggest that NINJA modulates JAZ dimerization. This study advances our understanding of JA signaling by providing insights into the dynamics, interactions, and structure of the JAZ-NINJA core of the JA repressor complex.

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WIZ

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