CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia

Joshua D Hansen; Matthew Correa; Matt Alexander; Mark Nagy; Dehua Huang; John Sapienza; Gang Lu; Laurie A LeBrun; Brian E Cathers; Weihong Zhang; Yang Tang; Massimo Ammirante; Rama K Narla; Joseph R Piccotti; Michael Pourdehnad; Antonia Lopez-Girona

doi:10.1021/acs.jmedchem.0c01489

CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia

J Med Chem. 2021 Feb 25;64(4):1835-1843. doi: 10.1021/acs.jmedchem.0c01489. Epub 2021 Feb 16.

Authors

Affiliations

¹ Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
² Bristol Myers Squibb, 556 Morris Avenue, Summit, New Jersey 07901, United States.
³ Bristol Myers Squibb, 1500 Owens Street, Suite 600, San Francisco, California 94158, United States.

PMID: 33591756
DOI: 10.1021/acs.jmedchem.0c01489

Abstract

Acute myeloid leukemia (AML) is marked by significant unmet clinical need due to both poor survival and high relapse rates where long-term disease control for most patients with relapsed or refractory AML remain dismal. Inspired to bring novel therapeutic options to these patients, we envisioned protein degradation as a potential therapeutic approach for the treatment of AML. Following this course, we discovered and pioneered a novel mechanism of action which culminated in the discovery of CC-90009. CC-90009 represents a novel protein degrader and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. This manuscript briefly summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and efficacy data for CC-90009, which is currently in phase 1 clinical development.

MeSH terms

Acetamides / chemistry
Acetamides / pharmacology
Acetamides / therapeutic use*
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Humans
Isoindoles / chemistry
Isoindoles / pharmacology
Isoindoles / therapeutic use*
Leukemia, Myeloid, Acute / drug therapy*
Macaca fascicularis
Male
Mice
Molecular Structure
Peptide Termination Factors / antagonists & inhibitors*
Peptide Termination Factors / chemistry
Peptide Termination Factors / metabolism
Piperidones / chemistry
Piperidones / pharmacology
Piperidones / therapeutic use*
Proteolysis / drug effects
Structure-Activity Relationship
Ubiquitin-Protein Ligases / metabolism*

Substances

Acetamides
Adaptor Proteins, Signal Transducing
Antineoplastic Agents
CC-90009
CRBN protein, human
Crbn protein, mouse
Isoindoles
Peptide Termination Factors
Piperidones
peptide-chain-release factor 3
Ubiquitin-Protein Ligases