Discovery of 9H-pyrimido[4,5-b]indole derivatives as dual RET/TRKA inhibitors
Baku Acharya1, Debasmita Saha2, Noemi Garcia Garcia3
1Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Abstract:
Aberrant RET kinase signaling is activated in numerous cancers including lung, thyroid, breast, pancreatic, and prostate. Recent approvals of selective RET inhibitors, pralsetinib and selpercatinib, has shifted the focus of RET kinase drug discovery programs towards the development of selective inhibitors. However, selective inhibitors invariably lose efficacy as the selective nature of the inhibitor places Darwinian-like pressure on the tumor to bypass treatment through the selection of novel oncogenic drivers. Further, selective inhibitors are restricted for use in tumors with specific genetic backgrounds that do not encompass diverse patient classes. Here we report the identification of a pyrimido indole RET inhibitor found to also have activity against TRK. This selective dual RET/TRK inhibitor can be utilized in tumors with both RET and TRK genetic backgrounds and can also provide blockade of NTRK-fusions that are selected for from RET inhibitor treatments. Efforts towards developing dual RET/TRK inhibitors can be beneficial in terms of encompassing more diverse patient classes while also achieving blockade against emerging resistance mechanisms.
Insights
Researchers identified a novel dual RET/TRK inhibitor effective against various cancers. This new drug overcomes resistance to selective RET inhibitors and broadens treatment options for diverse patient populations.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Aberrant RET kinase signaling drives numerous cancers, including lung, thyroid, breast, pancreatic, and prostate.
- Selective RET inhibitors (pralsetinib, selpercatinib) are approved but face challenges with acquired resistance and limited patient applicability.
- Tumor evolution under selective pressure can lead to novel oncogenic drivers, diminishing drug efficacy.
Purpose of the Study:
- To identify novel inhibitors targeting RET kinase with potential activity against TRK.
- To develop a dual RET/TRK inhibitor capable of treating diverse genetic backgrounds and overcoming resistance mechanisms.
- To explore therapeutic strategies that encompass broader patient classes and block emerging resistance pathways.
Main Methods:
- Identification and characterization of a novel pyrimido indole compound.
- Assessment of the inhibitor's activity against both RET and TRK kinases.
- Evaluation of the inhibitor's efficacy in preclinical models of RET-driven and TRK-driven cancers.
- Analysis of the inhibitor's potential to overcome resistance mechanisms, including NTRK-fusions.
Main Results:
- A novel pyrimido indole compound with dual RET/TRK inhibitory activity was identified.
- The dual inhibitor demonstrates efficacy in tumors with both RET and TRK genetic alterations.
- The compound effectively blocks NTRK-fusions that emerge as resistance mechanisms to selective RET inhibitors.
- This dual-targeting approach broadens the applicability of RET-targeted therapies.
Conclusions:
- Dual RET/TRK inhibitors represent a promising therapeutic strategy for a wider range of cancer patients.
- This approach can overcome acquired resistance driven by novel oncogenic drivers, such as NTRK-fusions.
- Developing dual inhibitors enhances treatment inclusivity across diverse patient populations and combats evolving resistance mechanisms in cancer therapy.
