Authors: Matthew Stecher, Terungwa Iorkula, Matt A. Peterson
Mentors: Matt A. Peterson
Insitution: Brigham Young University
Tropomyosin Receptor Kinase (TRK) inhibition has become an effective therapeutic approach for treatment of a variety of cancers including soft tissue sarcoma, pilocytic astrocytoma, non-small cell lung cancers, colorectal cancers, glioblastomas, pediatric gliomas, papillary thyroid cancers, and secretory breast carcinoma. Despite the successful use of first-generation TRK inhibitors Larotrectinib and Entrectinib which have shown significant therapeutic response in patients, acquired resistance to these drugs has emerged and is creating serious barriers to maintaining long-term therapeutic efficacy. A common mechanism for acquired resistance is associated with the emergence of mutations. Hence, mutation-induced drug resistance continues to be a major challenge for both first- and second-generation TRK inhibitors. Here, we present the design of novel macrocyclic 3,5-diaminated pyrazolo[1,5-a] pyrimidine ligands with high potential for combating drug-resistant disease.