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
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Acetamides / chemistry
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Acetamides / pharmacology
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Acetamides / therapeutic use*
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Apoptosis / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Humans
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Isoindoles / chemistry
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Isoindoles / pharmacology
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Isoindoles / therapeutic use*
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Leukemia, Myeloid, Acute / drug therapy*
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Macaca fascicularis
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Male
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Mice
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Molecular Structure
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Peptide Termination Factors / antagonists & inhibitors*
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Peptide Termination Factors / chemistry
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Peptide Termination Factors / metabolism
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Piperidones / chemistry
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Piperidones / pharmacology
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Piperidones / therapeutic use*
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Proteolysis / drug effects
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Structure-Activity Relationship
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Ubiquitin-Protein Ligases / metabolism*
Substances
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Acetamides
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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CC-90009
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CRBN protein, human
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Crbn protein, mouse
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Isoindoles
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Peptide Termination Factors
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Piperidones
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peptide-chain-release factor 3
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Ubiquitin-Protein Ligases