Identification of Thieno[3,2-d]pyrimidine derivatives as dual FAK and FLT-3 Inhibitors
Focal adhesion kinase (FAK) is overexpressed in metastatic cancers. Thieon[3,2- d]pyrimidine derivatives were designed and synthesized as novel FAK inhibitors. However, SAR driven approach led to the lead molecule 26 that showed promising inhibitory activity also against FMS-like tyrosine kinase (FLT-3) mutants.
Additionally, 26 showed good apoptotic activity, growth inhibition and tumor reduction in MDA-MB-231 xenograft model . Also, 26 demonstrated tumor suppression in MV-4-11 xenograft model suggesting this compound to be effective against acute myeloid leukemia (AML).
Proposed docking of 26 on FAK
Proposed docking of 26 on FLT-3
THERAINDX has the experience of quickly building the SAR and design of hit and then lead molecules in order to have the dual potency based on the synergy of the targets. Also, we have the computational chemistry support to further validate the hypothesis followed by in-vitro, DMPK and xenograft study models.
- 1. Taebo Sim et. al. Identification of Thieno[3,2-d]pyrimidine derivatives as dual FAK and FLT-3 Inhibitors. J. Med. Chem. 2021 64 (16), 11934-11957
- 2. McLean G. W. et. al. The role of focal-adhesion kinase in cancer – a new therapeutic opportunity. Nat. Rev. Cancer 2005, 5, 505-515.
- Author : Dr. Sachin Madan- Director Medicinal Chemistry
