2. Academic Validation
  3. Discovery of 9H-pyrimido[4,5-b]indole derivatives as dual RET/TRKA inhibitors

Discovery of 9H-pyrimido[4,5-b]indole derivatives as dual RET/TRKA inhibitors

  • Bioorg Med Chem. 2024 May 15:106:117749. doi: 10.1016/j.bmc.2024.117749.
Baku Acharya 1,  Debasmita Saha 2,  Noemi Garcia Garcia 3,  Daniel Armstrong 1,  Baha'a Jabali 1,  Maha Hanafi 4,  Brendan Frett 5,  Katie Rose Ryan 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • 2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Conrad Prebys Centre for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA, USA.
  • 3 Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11526, Egypt.
  • 5 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address: BAFrett@uams.edu.
  • 6 Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address: KRRyan@uams.edu.
PMID: 38744018 DOI: 10.1016/j.bmc.2024.117749
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.

Keywords

Drug discovery; Kinase; Medicinal chemistry; Polypharmacology; RET; Small molecule; TRK.

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