The 3H-pyrazolo[4,3-f]quinoline core, a privileged fusion moiety from quinoline and indazole, facilely synthesized in a one flask multi-component Doebner–Povarov reaction, is a newly described kinase hinge binder.
A narrow selectivity profile, limited metabolism and a reliable SAR suggest the little explored biphenyl pyrazoyl-urea scaffold as a promising chemotype for the development of FLT3-targeting drugs for the treatment of AML.
The development of macrocycles has emerged as an innovative approach to improve kinase inhibitor selectivity, as well as pharmacokinetic and pharmacodynamic properties.
Novel FLT3/CHK1 dual agents, the representative compound 30, with favorable oral PK properties, can overcome multiple FLT3-TKD and FLT3-ITD mutations.
A novel and selective ATR inhibitor, GBA-16-24, was developed. It exhibits potent synthetic lethality in FLT3-mutated AML and synergizes with clinical FLT3 inhibitors, proposing a promising combination therapy.