Design, synthesis and biological evaluation of macrocyclic NTRK heterobifunctional degraders

  • Bioorg Med Chem Lett. 2026 Apr:133:130516. doi: 10.1016/j.bmcl.2025.130516.
Corey Anderson  1 ,  Jennifer Han-Chun Tsai  2 ,  Oscar Ingham  2 ,  Richard W Deibler  2 ,  Bridget Kreger  2 ,  Prasoon Chaturvedi  2 ,  Ka Ying Sharon Hung  2 ,  Christopher G Nasveschuk  2 ,  James A Henderson  2 ,  Mathew E Sowa  2
Affiliations
  • 1. C4 Therapeutics, 490 Arsenal Way, Suite 120, Watertown, MA 02472, USA. Electronic address: [email protected].
  • 2. C4 Therapeutics, 490 Arsenal Way, Suite 120, Watertown, MA 02472, USA.
PMID: 41483860 DOI: 10.1016/j.bmcl.2025.130516
Abstract

Aberrant NTRK gene fusions leading to constitutively activated NTRK proteins are a key driver for a range of adult and pediatric tumors. Small molecule NTRK inhibitors targeting the NTRK ATP site have shown success in the clinic resulting in two approved drugs. Unfortunately, resistance mutations have created the need for additional therapies. In this study, we detail the design, synthesis, and evaluation of novel NTRK BiDAC™ degraders containing a macrocyclic, mutant active, NTRK targeting ligand.

Keywords
Exit vector analysis; Heterobifunctional degraders; Macrocycles; NTRK; Protein degradation; Ternary complex.
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