Pyrrolo[2,3-d]pyrimidine derivatives as inhibitors of RET: Design, synthesis and biological evaluation

Discovery of N-Trisubstituted Pyrimidine Derivatives as Type I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose

“…As mentioned previously, we expected this series to be type II inhibitors of the RET kinase with the R3 group going into the allosteric pocket created in the DFG-out (inactive) conformation. We also expected the SAR at R3 to be consistent with the type II RET inhibitor series we previously reported . However, we observed no similarity in the SAR.…”

“…Enzymatic activities were measured using Caliper EZ Reader II (PerkinElmer, Walthman, MA) with a 12-sipper chip as described previously. , The microfluidic assay monitoring the separation of the phosphorylated product from substrate was applied. The separation buffer used in the running system was 100 mM HEPES, 10 mM EDTA, 0.015% Brij-35, 0.1% CR-3 (PerkinElmer, Walthman, MA).…”

“…Pz-1, a clinical drug candidate from our lab with dual RET–VEGFR2 activity, and its second-generation derivative NPA101.3 were described. Recently we also reported a structure–activity relationship (SAR) study of pyrrolo­[2,3- d ]­pyrimidine-based ATP noncompetitive RET inhibitors . All these RET inhibitors bind to the inactive conformation (type II) of the RET kinase and have a bicyclic core that binds to the hinge residues of the kinase.…”

Targeting Rearranged during Transfection in Cancer: A Perspective on Small-Molecule Inhibitors and Their Clinical Development

“…RET is a targetable kinase, and many studies have investigated the use of both multikinase inhibitors (MKIs) as well as RET-specific inhibitors as therapeutic strategies. Our previous efforts and continuous interest in RET inhibitors prompted us to compile a detailed review of RET and RET inhibitors developed to pharmacologically modulate RET signaling in RET-driven malignancies. − …”

Discovery of pyrazolo-thieno[3,2-d]pyrimidinylamino-phenyl acetamides as type-II pan-tropomyosin receptor kinase (TRK) inhibitors: Design, synthesis, and biological evaluation

“…As a part of our continuous effort on the development of kinase inhibitors, [25][26][27][28][29][30] especially TRKA inhibitors, [31] we recently screened a small in-house kinase compounds library, and compounds 1b and 2b were found to exhibit moderate TRKA inhibitory activity. Although thienopyrimidines derivatives had been reported having a variety of biological activities including anti-parasitic activity [32]; Bertrand et al, disclosed the co-crystal structure of EX429 with TRKA and TRKB, [33] but the medicinal chemistry effort towards the discovery of this compound remained unknown.…”