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Last update 23 Jan 2025

WIZ

Last update 23 Jan 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

647

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 ; Cobb, Jennifer S. ; Ornelas, Elizabeth ; Mao, Xiaohong ; Dales, Natalie A. ; Kerrigan, John Ryan ; Pizzato, Nicolas ; Lin, James ; 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 May 2024·Microbiological Research

Mechanisms on salt tolerant of Paenibacillus polymyxa SC2 and its growth-promoting effects on maize seedlings under saline conditions

Article

Author: Wang, Chengqiang ; Zhang, Yanan ; Zhu, Xiuling ; Zhao, Dongying ; Li, Hui ; Li, Wenjie ; Pei, Jian ; Liu, Kai ; Wang, Zhongyue ; Jiang, Juquan ; Wang, Yanjun ; Du, Binghai

Soil salinity negatively affects microbial communities, soil fertility, and agricultural productivity and has become a major agricultural problem worldwide. Plant growth-promoting rhizobacteria (PGPR) with salt tolerance can benefit plant growth under saline conditions and diminish the negative effects of salt stress on plants. In this study, we aimed to understand the salt-tolerance mechanism of Paenibacillus polymyxa at the genetic and metabolic levels and elucidate the mechanism of strain SC2 in promoting maize growth under saline conditions. Under salt stress, we found that strain SC2 promoted maize seedling growth, which was accompanied by a significant upregulation of genes encoding for the biosynthesis of peptidoglycan, polysaccharide, and fatty acid, the metabolism of purine and pyrimidine, and the transport of osmoprotectants such as trehalose, glycine betaine, and K⁺ in strain SC2. To further enhance the salt resistance of strain SC2, three mutants (SC2-11, SC2-13, and SC2-14) with higher capacities for salt resistance and exopolysaccharide synthesis were obtained via atmospheric and room-temperature plasma mutagenesis. In saline-alkaline soil, the mutants showed better promoting effect on maize seedlings than wild-type SC2. The fresh weight of maize seedlings was increased by 68.10% after treatment with SC2-11 compared with that of the control group. The transcriptome analysis of maize roots demonstrated that SC2 and SC2-11 could induce the upregulation of genes related to the plant hormone signal transduction, starch and sucrose metabolism, reactive oxygen species scavenging, and auxin and ethylene signaling under saline-alkaline stress. In addition, various transcription factors, such as zinc finger proteins, ethylene-responsive-element-binding protein, WRKY, myeloblastosis proteins, basic helix-loop-helix proteins, and NAC proteins, were up-regulated in response to abiotic stress. Moreover, the microbial community composition of maize rhizosphere soil after inoculating with strain SC2 was varied from the one after inoculating with mutant SC2-11. Our results provide new insights into the various genes involved in the salt resistance of strain SC2 and a theoretical basis for utilizing P. polymyxa in saline-alkaline environments.

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