2,7-Disubstituted-pyrrolo[2,1-f][1,2,4]triazines: New Variant of an Old Template and Application to the Discovery of Anaplastic Lymphoma Kinase (ALK) Inhibitors with in Vivo Antitumor Activity

Abstract

A novel 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine scaffold has been designed as a new kinase inhibitor platform mimicking the bioactive conformation of the well-known diaminopyrimidine motif. The design, synthesis, and validation of this new pyrrolo[2,1-f][1,2,4]triazine scaffold will be described for inhibitors of anaplastic lymphoma kinase (ALK). Importantly, incorporation of appropriate potency and selectivity determinants has led to the discovery of several advanced leads that were orally efficacious in animal models of anaplastic large cell lymphoma (ALCL). A lead inhibitor (30) displaying superior efficacy was identified and in depth in vitro/in vivo characterization will be presented.

The EGFR family members sustain the neoplastic phenotype of ALK+ lung adenocarcinoma via EGR1

“…Alternatively, cells (ALK+ and ALK− (H1395)) were treated with ALK-selective inhibitors (CEP-14083 and CEP-26939, from Cephalon/Teva, West Chester, PA, USA). 28, 29 ALK inhibition led to a significant decrease in the phosphorylation of known ALK downstream targets (STAT3, Erk1/2, Shp2 and Akt; Supplementary Figure 1A). 24 As expected, ablation of ALK signaling was associated with growth impairment (Figure 1c and Supplementary Figure 1B) and a very high rate of apoptosis for the H3122 cells (Figure 1d and Supplementary Figure 1C).…”

Anaplastic lymphoma kinase inhibitors as anticancer therapeutics: a patent review

“…Nonetheless, the hinge binding D-A motif specific to DAPs is preserved. To the best of our knowledge, this is the first time 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine kinase inhibitors are exemplified [71]. Two potent and selective ALK inhibitors (38 and 39, Figure 8) were published and have shown excellent PD responses and efficacies in NPM-ALK + ALCL xenografts with good ADME properties [71,74].…”

“…Pyrrolopyrimidines from Abbott [69] have the 5-membered ring replace the C-5-Cl and C-6-H (pyrimidine numbering) of DAPs, adding another potential H-bond donor (the pyrrole NH) to the core to form a D-A-D registry for putative 2,7-Substituted pyrrolotriazines discovered at Cephalon/ Teva [70] constitute an inventive variation on a previously known heteroaromatic system. Pyrrolo[2,1-f][1,2,4]triazine inhibitors of ALK [71], JAK2 or FAK [72,73] are exemplified. Here, the pyrrole ring replaces the C-5-Cl and C-4-NH of DAPs, serving as a platform for the C-7 substituent (38 in Figure 8 for numbering), while the pyrrole nitrogen becomes a bridgehead atom, rendering the 6-member ring a triazine instead of pyrimidine.…”

“…To the best of our knowledge, this is the first time 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine kinase inhibitors are exemplified [71]. Two potent and selective ALK inhibitors (38 and 39, Figure 8) were published and have shown excellent PD responses and efficacies in NPM-ALK + ALCL xenografts with good ADME properties [71,74]. An optimized synthetic route to this scaffold was also developed in collaboration with the internal process chemistry group [75].…”

Pyrrolo[2,1-f][1,2,4]triazine: a promising fused heterocycle to target kinases in cancer therapy

“…Axitinib, Brigatinib, Ceritinib, Crizotinib, Lorlatinib are the FDA-approved ALK inhibitors currently in clinical use for the treatment of NSCLC [ 37 ]. Ott et al synthesized 2,7-disubstituted-pyrrolo[2,1- f ][1,2,4]triazine scaffold containing molecules as potent ALK inhibitors [ 93 ]. Many compounds displayed well in vitro as well as in vivo efficacy.…”