Pyrrolo[2,3-d]pyrimidine derivatives as inhibitors of RET: Design, synthesis and biological evaluation
| Autor: | Naresh Gunaganti, Yuet-Kin Leung, Lingtian Zhang, Naga Rajiv Lakkaniga, Brendan Frett, Hong-yu Li, Binyam Belachew |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities endocrine system endocrine system diseases Pyrimidine Antineoplastic Agents Chemistry Techniques Synthetic 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Cell Movement Cell Line Tumor Drug Discovery Structure–activity relationship Humans Pyrroles neoplasms Protein Kinase Inhibitors 030304 developmental biology Cell Proliferation Pharmacology 0303 health sciences 010405 organic chemistry Kinase Point mutation Organic Chemistry Proto-Oncogene Proteins c-ret General Medicine 0104 chemical sciences Pyrimidines chemistry Biochemistry Cell culture Drug Design Bioisostere Growth inhibition Lead compound |
| Zdroj: | European journal of medicinal chemistry. 206 |
| ISSN: | 1768-3254 |
| Popis: | Gene fusions and point mutations of RET kinase are crucial for driving thoracic cancers, including thyroid cancer and non-small cell lung cancer. Various scaffolds based on different heterocycles have been synthesized and evaluated as RET inhibitors. In this work, we investigate pyrrolo[2,3-d]pyrimidine derivatives for inhibition of RET-wt, drug resistant mutant RET V804M and RET gene fusion driven cell lines. Several compounds were synthesized and the structure activity relationship was extensively studied to optimize the scaffold. Thieno[2,3-d]pyrimidine, a bioisostere of pyrrolo[2,3-d]pyrimidine, was also explored for the effect on RET inhibition. We identified a lead compound, 59, which shows low nanomolar potency against RET-wt and RET V804M. Further 59 shows growth inhibition of LC-2/ad cells which RET-CCDC6 driven. We also determined that 59 is a type 2 inhibitor of RET and demonstrated its ability to inhibit migration of tumor cells. Based on computational studies, we proposed a binding pose of 59 in RET pocket and have quantified the contributions of individual residues for its binding. Together, 59 is an important lead compound which needs further evaluation in biological studies. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect