Optimization of 4-Phenylamino-3-quinolinecarbonitriles as Potent Inhibitors of Src Kinase Activity

Abstract

Subsequent to the discovery of 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile (1a) as an inhibitor of Src kinase activity (IC(50) = 30 nM), several additional analogues were prepared. Optimization of the C-4 anilino group of 1a led to 1c, which contains a 2,4-dichloro-5-methoxy-substituted aniline. Replacement of the methoxy group at C-7 of 1c with a 3-(morpholin-4-yl)propoxy group provided 2c, resulting in increased inhibition of both Src kinase activity and Src-mediated cell proliferation. Analogues of 2c with other trisubstituted anilines at C-4 were also potent Src inhibitors, and the propoxy group of 2c was preferred over ethoxy, butoxy, or pentoxy. Replacement of the morpholine group of 2c with a 4-methylpiperazine group provided 31a, which had an IC(50) of 1.2 nM in the Src enzymatic assay, an IC(50) of 100 nM for the inhibition of Src-dependent cell proliferation and was selective for Src over non-Src family kinases. Compound 31a, which had higher 1 and 4 h plasma levels than 2c, effectively inhibited tumor growth in xenograft models.

SKI-606 (Bosutinib) Blocks Prostate Cancer Invasion, Growth, and Metastasis In vitro and In vivo through Regulation of Genes Involved in Cancer Growth and Skeletal Metastasis

“…Because of this, several small molecule Src inhibitors are in early clinical development (10)(11)(12). Of particular interest is the ability of these inhibitors to block organ-specific metastases (13,18,25).…”

“…The Src inhibitor 4-amino-5-(4-chlorophenyl)-7-(1-butyl)pyrazolo [3,4-alpha]pyrimidine decreased tumor growth and metastasis in a xenograft model of pancreatic cancer (9). Other small molecule Src inhibitors are in clinical development (10)(11)(12). Among these, the multikinase inhibitor dasatinib has shown efficacy in several preclinical models, including chronic myelogenous leukemia (CML) and pancreatic and prostate cancer, and is approved for treating imatinib resistant or intolerant CML (2,(12)(13)(14).…”

“…Among these, the multikinase inhibitor dasatinib has shown efficacy in several preclinical models, including chronic myelogenous leukemia (CML) and pancreatic and prostate cancer, and is approved for treating imatinib resistant or intolerant CML (2,(12)(13)(14). Another small molecule Src inhibitor, SKI-606 (Bosutinib), was initially shown to inhibit CML and colon tumor growth in nude mice (10,(15)(16)(17). In studies carried out by us and others (18,19), SKI-606 inhibited human breast cancer cell proliferation, invasion and migration in vitro.…”

Evolving treatment strategies for patients newly diagnosed with chronic myeloid leukemia: the role of second-generation BCR–ABL inhibitors as first-line therapy

“…[8][9][10][11][12][13][14] Like imatinib, nilotinib binds an inactive conformation of BCR-ABL; however, because of an improved topographical fit, binding affinity is increased for ABL kinase but reduced in relative terms for other shared kinase targets, such as platelet-derived growth factor receptor. Compared with imatinib, nilotinib is 10-50-fold more potent in inhibiting proliferation of BCR-ABL-expressing cell lines.…”

“…3 An earlier IRIS analysis found that no patient with both a CCyR and MMR at 12 months had transformed to AP/BP at 5 years, compared with 5% of patients with a CCyR but no MMR (P ¼ 0.007). 1,47 Although analyses Table 1 Comparison of the potency and selectivity of imatinib, dasatinib, nilotinib and bosutinib for BCR-ABL in vitro [8][9][10][11][12][13][14] Fold increase in potency against BCR-ABL in cellular proliferation assays relative to imatinib Comparative potency against BCR-ABL, PDGFRb, KIT and SRC based on IC 50 values in proliferation/kinase assays from IRIS and Hammersmith cohorts found no TFS advantage for patients who achieved CCyR and MMR at 18 months compared with patients who achieved CCyR alone, achieving a MMR by 12-18 months in both cohorts significantly reduced the probability of losing CCyR. 1,3,48 Thus, if faster responses and higher response rates can be achieved with alternative strategies, such as more potent BCR-ABL inhibitors, this may improve longer-term outcomes in patients with newly diagnosed CML-CP.…”