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Published on: May 15, 2019
Discovery of an orally bioavailable, CNS active pan-mutant RET kinase heterobifunctional degrader
Douglas L Orsi1, Kiel E Lazarski1, Reina Improgo1
1C4 Therapeutics 490 Arsenal Way, Suite 120 Watertown MA 02472 USA jhenderson@c4therapeutics.com.
Abstract:
Point mutations and chromosomal fusions of the Rearranged During Transfection (RET) transmembrane receptor tyrosine kinase cause constitutive substrate-free activation, driving numerous human cancers. RET-selective kinase inhibitors (selpercatinib, pralsetinib) are in current clinical use for RET-driven tumors. However, the emergence of resistance mutations, such as those at the solvent-front G810 residue, results in reduced efficacy. We sought to exploit the event-driven pharmacology of targeted protein degradation to achieve pan-mutant activity against RET-driven cancers with a single selective RET degrader, while utilizing non-phthalimide cereblon (CRBN) ligands to discover orally bioavailable heterobifunctional degraders. Here we describe the medicinal chemistry efforts that led to compound 20, an orally bioavailable, brain-penetrant, pan-mutant and pan-fusion RET heterobifunctional degrader.
Insights
Researchers developed a novel drug, compound 20, to combat cancers driven by the Rearranged During Transfection (RET) gene. This targeted protein degrader effectively targets various RET mutations and fusions, offering a new treatment option for RET-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Rearranged During Transfection (RET) gene alterations drive many human cancers.
- Current RET-targeted therapies face resistance due to mutations like G810.
- Targeted protein degradation offers a strategy to overcome drug resistance.
Purpose of the Study:
- To develop a single, orally bioavailable drug with pan-mutant and pan-fusion activity against RET-driven cancers.
- To utilize non-phthalimide cereblon (CRBN) ligands for novel heterobifunctional degrader discovery.
- To overcome resistance mechanisms associated with existing RET inhibitors.
Main Methods:
- Medicinal chemistry efforts focused on designing heterobifunctional degraders.
- Exploitation of event-driven pharmacology and targeted protein degradation.
- Utilized non-phthalimide cereblon (CRBN) ligands to achieve oral bioavailability and brain penetrance.
Main Results:
- Discovery of compound 20, a novel RET heterobifunctional degrader.
- Compound 20 demonstrates oral bioavailability and brain penetrance.
- Achieved pan-mutant and pan-fusion activity against RET alterations.
Conclusions:
- Compound 20 represents a promising therapeutic candidate for RET-driven cancers, including those with resistance mutations.
- Targeted protein degradation using novel ligands is effective against challenging cancer targets.
- This approach offers a potential strategy to overcome acquired resistance to kinase inhibitors.
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