Delving into the Latest Updates on ABD957 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

ABHD17A

Action

inhibitors

Mechanism

ABHD17A inhibitors(abhydrolase domain containing 17A, depalmitoylase inhibitors)

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

Myeloid Leukemia

Inactive Indication-

Originator Organization

The Scripps Research Institute

Active Organization

The Scripps Research Institute

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC27H36F3N7O5S

InChIKeyISNXAOFEMNFJCO-XTWGIRIWSA-N

CAS Registry3007772-60-0

Author: Zambetti, Noemi A ; Firestone, Ari J ; Hanigan, Thomas W ; Richardson, Stewart K ; Predovic, Marina ; Remsberg, Jarrett R ; Dix, Melissa M ; Howell, Amy R ; Cravatt, Benjamin F ; Niphakis, Micah J ; Long, Amanda ; Suciu, Radu M ; Inguva, Anagha ; Huang, Ben ; Ngo, Nhi ; Henry, Cassandra L ; Lum, Kenneth M ; Shannon, Kevin

Multiple Ras proteins, including N-Ras, depend on a palmitoylation/depalmitoylation cycle to regulate their subcellular trafficking and oncogenicity. General lipase inhibitors such as Palmostatin M (Palm M) block N-Ras depalmitoylation, but lack specificity and target several enzymes displaying depalmitoylase activity. Here, we describe ABD957, a potent and selective covalent inhibitor of the ABHD17 family of depalmitoylases, and show that this compound impairs N-Ras depalmitoylation in human acute myeloid leukemia (AML) cells. ABD957 produced partial effects on N-Ras palmitoylation compared with Palm M, but was much more selective across the proteome, reflecting a plasma membrane-delineated action on dynamically palmitoylated proteins. Finally, ABD957 impaired N-Ras signaling and the growth of NRAS-mutant AML cells in a manner that synergizes with MAP kinase kinase (MEK) inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes as regulators of the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers.

100 Deals associated with ABD957

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