N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a Novel, Highly Selective, Orally Available, Dual-Specific c-Src/Abl Kinase Inhibitor

Abstract

Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. We report here a novel subseries of C-5-substituted anilinoquinazolines that display high affinity and specificity for the tyrosine kinase domain of the c-Src and Abl enzymes. These compounds exhibit high selectivity for SFKs over a panel of recombinant protein kinases, excellent pharmacokinetics, and in vivo activity following oral dosing. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine (AZD0530) inhibits c-Src and Abl enzymes at low nanomolar concentrations and is highly selective over a range of kinases. AZD0530 displays excellent pharmacokinetic parameters in animal preclinically and in man (t(1/2) = 40 h). AZD0530 is a potent inhibitor of tumor growth in a c-Src-transfected 3T3-fibroblast xenograft model in vivo and led to a significant increase in survival in a highly aggressive, orthotopic model of human pancreatic cancer when dosed orally once daily. AZD0530 is currently undergoing clinical evaluation in man.

Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells

“…Our data demonstrates that combining tamoxifen with the novel Src/Abl inhibitor, AZD0530 [20], improves the growth-inhibitory response seen with each treatment alone. Moreover, whereas long-term treatment with each agent alone resulted in the acquisition of a resistant state as demonstrated by a regain in growth ability in the presence of the drug, cells exposed to the combination of tamoxifen and AZD0530 did not acquire resistance; rather, complete cell loss was observed following such treatments in two Table 2 RT-PCR analysis of proliferation-related gene expression was performed with subsequent densitometric analysis of PCR products independent ER-positive cell lines (MCF7 and T47D).…”

“…In this report, we demonstrate that combined targeting of the ER and Src kinase using tamoxifen and the novel Src inhibitor, AZD0530 [20] in two separate, ERpositive breast cancer cell lines, greatly enhances the growth inhibitory effects seen with either agent alone, preventing the development of acquired tamoxifen resistance.…”

“…Despite Src activity remaining suppressed in AZD0530-resistant cells, little is known concerning the activity of other Src family kinases in such cells. Although AZD0530 is known to inhibit the Src family kinase Yes [20], it remains to be determined whether there is a role for other members of the Src family in AZD0530-resistant cells and their contribution to their proliferative capacity.…”

c-Src protein kinase inhibitors block assembly and maturation of dengue virus

“…This result included Src family inhibitors from the pyrimidopyrimidine compound class (K003), the quinazoline class (K030), the indoyl sulfonamide compound K117, as well as Kenpaullone (K144), and Lavendustins A (K028) and C (K115) (SI Table 3). This group of six compounds included two clinical stage candidates: dasatinib (SPRYCEL, K005), a thiazolylaminopyrimidine compound currently approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML) (15,16) and AZD0530 (K045), a quinazoline which is currently being tested in solid tumors and leukemia (17). Because of their respective stages of clinical development, we were particularly interested in understanding the mechanism responsible for the anti-DENV activity of these compounds.…”

“…AZD0530 is a considerably more selective kinase inhibitor, exhibiting potent activity across the Src-family of kinases and has even been shown to be Ϸ10-fold more active against Src family kinases (IC 50 1-5 nM) than against Abl kinase (17). Although dasatinib and AZD0530 target other cellular kinases, the association of Src kinase activity with DENV infection prompted us to focus our follow-up efforts on the role of Src family kinases in the postentry steps of DENV infection and replication.…”