Design, synthesis and pharmacological evaluation of ALK and Hsp90 dual inhibitors bearing resorcinol and 2,4-diaminopyrimidine motifs

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…This hybridization approach is also nicely illustrated by the identification of bifunctional ALK‐Hsp90 inhibitors 163 and 164 (derived from 161 and 162 ) and MEK‐PI3K inhibitor 167 (ST‐168, derived from 165 and 166 )…”

Evolution of kinase polypharmacology across HSP90 drug discovery

“…More recently, a computational analysis of pharmacological databases uncovered these and a few other dual inhibitors of HSP90 and kinases (Anighoro et al, 2015). In the last few years four studies have rationally designed dual inhibitors of HSP90 together with PDKs (Tso et al, 2014), BCR-ABL (Wu et al, 2015), or ALK (Geng et al, 2018), and also a triple inhibitor of HSP90, JAKs, and HDAC (Yao et al, 2018), although the last two of these (Geng et al, 2018;Yao et al, 2018) have used pharmacophore linking rather than merging. Despite the above evidence of cross-pharmacology between HSP90 and kinases, the kinase polypharmacology of HSP90 clinical candidates has not been systematically characterized and represents a very interesting area that we felt should be explored in greater depth and scale.…”

Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitors

“…ALK has received a great deal of attention as a promising therapeutic target for targeted cancer therapy and, as a result, enormous efforts have been devoted to developing ALK inhibitors. While various scaffolds such as pyrimidine, aminopyridine 8,9 , benzo[b]carbazolone 10 , indazole 11 have been exploited to identify new ALK inhibitors, 2,4-diarylamino pyrimidines 2,[12][13][14][15][16][17][18][19][20][21] have been the most common molecular platform for discovering ALK inhibitors including ceritinib and brigatinib. Crizotinib 22,23 was approved in 2011 as an ALK inhibitor for treatment of NSCLC patients harbouring EML4-ALK fusion oncogene.…”

“…In 2018, crizotinib was given a breakthrough therapy designation to treat ALK-positive relapsed/ refractory anaplastic large cell lymphoma (ALCL) [24][25][26][27] patients. However, acquired secondary mutations (L1196M, G1269A, F1174L, S1206Y, 1151 T-ins, L1152R, C1156Y and G1202R) occurring in the ALK kinase domain resulted in resistance to crizotinib 18,20,[28][29][30] . The ALK gatekeeper mutation L1196M is the most frequent secondary mutation taking place in NSCLC patients and, consequently, a significant effort has been made to identify novel and potent L1196M inhibitors 31 .…”