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Antitarget Selectivity and Tolerability of Novel Pyrrolo[2,3-d]pyrimidine RET Inhibitors
Casey J N Mathison1, Yang Yang1, John Nelson1
1The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
Abstract:
The selective inhibition of RET kinase as a treatment for relevant cancer types including lung adenocarcinoma has garnered considerable interest in recent years and prompted a variety of efforts toward the discovery of small-molecule therapeutics. Hits uncovered via the analysis of archival kinase data ultimately led to the identification of a promising pyrrolo[2,3-d]pyrimidine scaffold. The optimization of this pyrrolo[2,3-d]pyrimidine core resulted in compound 1, which demonstrated potent in vitro RET kinase inhibition and robust in vivo efficacy in RET-driven tumor xenografts upon multiday dosing in mice. The administration of 1 was well-tolerated at established efficacious doses (10 and 30 mg/kg, po, qd), and plasma exposure levels indicated a minimal risk of KDR or hERG inhibition in vivo, as evaluated by Miles assay and free plasma concentrations, respectively.
Insights
Researchers developed a novel pyrrolo[2,3-d]pyrimidine compound (1) that effectively inhibits RET kinase. This compound shows potent in vitro activity and in vivo efficacy in RET-driven cancers, with good tolerability in mice.
Area of Science:
- Medicinal Chemistry
- Oncology
- Pharmacology
Background:
- Selective RET kinase inhibition is a promising strategy for treating cancers like lung adenocarcinoma.
- Discovery of small-molecule therapeutics targeting RET kinase is an active area of research.
Purpose of the Study:
- To identify and optimize novel small-molecule inhibitors of RET kinase.
- To evaluate the in vitro and in vivo efficacy and safety of a lead compound.
Main Methods:
- Analysis of archival kinase data to identify a pyrrolo[2,3-d]pyrimidine scaffold.
- Optimization of the scaffold to yield compound 1.
- In vitro kinase inhibition assays.
- In vivo efficacy studies in RET-driven tumor xenografts in mice.
- Toxicology assessments including Miles assay and plasma concentration analysis.
Main Results:
- Compound 1 demonstrated potent in vitro RET kinase inhibition.
- Compound 1 showed robust in vivo efficacy in RET-driven tumor xenografts.
- Compound 1 was well-tolerated at efficacious doses (10 and 30 mg/kg).
- Plasma exposure indicated minimal risk of KDR or hERG inhibition.
Conclusions:
- The optimized pyrrolo[2,3-d]pyrimidine compound 1 is a potent and efficacious RET kinase inhibitor.
- Compound 1 represents a promising therapeutic candidate for RET-driven cancers.
- The safety profile suggests a low risk of off-target inhibition at therapeutic doses.
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