Delving into the Latest Updates on HDAC/MLL1/WDR5 inhibitors(China Pharmaceutical University) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Compound 32d(China Pharmaceutical University)

Target

HDACs x MLL1 x WDR5

Action

inhibitors

Mechanism

HDAC inhibitors(Histone deacetylase inhibitors), MLL1 inhibitors(lysine methyltransferase 2A inhibitors), WDR5 inhibitors(WD repeat-containing protein 5 inhibitors)

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

Acute Myeloid Leukemia

Inactive Indication-

Originator Organization

China Pharmaceutical University

Active Organization

China Pharmaceutical University

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Targeting the WDR5-MLL1 protein-protein interaction (PPI) is considered to be an effective approach for the treatment of MLL-rearranged leukemia. However, interfering with WDR5-MLL1 PPI reduces methylated H3K4 levels and induces a decline in acetylated H3 levels, which may contribute to the suboptimal cellular efficacy of WDR5 inhibitors. We observed that cotreatment with WDR5-MLL1 PPI and HDAC inhibitors augmented the antiproliferative effect in MV-4-11 cells. Thus, a series of dual-target inhibitors was developed by merging the pharmacophores of the WDR5 and HDAC inhibitors. Among the developed inhibitors, compound 32d displayed an 89-fold increase in antiproliferative efficacy and induced potent cell apoptosis by impeding the DNA damage repair signaling pathway. Furthermore, the administration of 30 mg/kg of compound 32d was well tolerated, inhibiting MV-4-11 xenograft growth by 87.1%. Our investigation established the therapeutic effectiveness of the developed WDR5-MLL1/HDAC dual-target inhibitor against acute myeloid leukemia, providing a valuable tool for further exploration of crosstalk between the two targets.

100 Deals associated with HDAC/MLL1/WDR5 inhibitors(China Pharmaceutical University)

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