1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazoles:  Identification of a Potent Aurora Kinase Inhibitor with a Favorable Antitumor Kinase Inhibition Profile

Abstract

The optimization of a series of 5-phenylacetyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives toward the inhibition of Aurora kinases led to the identification of compound 9d. This is a potent inhibitor of Aurora kinases that also shows low nanomolar potency against additional anticancer kinase targets. Based on its high antiproliferative activity on different cancer cell lines, favorable chemico-physical and pharmacokinetic properties, and high efficacy in in vivo tumor models, compound 9d was ultimately selected for further development.

Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I

“…In addition, in kinase assays PHA-739358 had been shown to potently inhibit Aurora kinases A, B, and C indicating a pan-Aurora kinases inhibitory activity of this compound. 21 In analogy to other Aurora kinase inhibitors, PHA-739358 treatment resulted in accumulation of polyploid cells via endoreduplication. However, cells with a DNA content of greater than 4N were mainly found in BCR-ABL-negative BaF3 cells, whereas in BaF3-p210 cells, including their IM-resistant mutants, treatment with 0.2 M PHA-739358 generated polyploid cells and produced a marked loss of viability resulting from apoptosis, probably because of a predominance of the inhibitory effect on Bcr-Abl in these cells.…”

“…20 Here we report on in vitro studies performed with a novel kinase inhibitor, PHA-739358, which exhibits potent inhibitory activity against all 3 of the known Aurora kinases (A, B, and C) as well as Bcr-Abl tyrosine kinase. 21 To study the therapeutic potential of this new compound, we examined the antiproliferative and proapoptotic effects in IM-sensitive and -resistant leukemic cell lines. Furthermore, the efficacy of PHA-739358 was evaluated in primary CD34 ϩ cells derived from patients with newly diagnosed CML, in IM-resistant blast crisis, and from a patient harboring an IM-and dasatinib-resistant T315I mutation.…”

Analysis of Aurora B kinase in non-Hodgkin lymphoma

“…A number of small-molecule inhibitors with selectivity against Aurora A and/or Aurora B have been developed, including AZD1152 (a potent and selective inhibitor of Aurora B), MLN8054 33 (an orally available selective inhibitor of Aurora A), together with MK-0457, 34 and PHA-739358 35 (a pan-Aurora kinase inhibitor). These inhibitors are undergoing evaluation in clinical trials.…”

Synthesis and antileishmanial activity of new 1-aryl-1H-pyrazole-4-carboximidamides derivatives

“…5 Pyrazoles are a class of heterocyclic compounds that exhibit a broad spectrum of biological activities such antiinflamatory, antimicrobial and antitumor. 6 Consequently, a large number of synthetic routes to pyrazoles have been reported and summarized in some monographs and reviews. 7,8 These reports have been useful for biologists and chemists engaged in the development of new drugs and/or synthetic routes.…”