Src inhibitor

D. J. Maly, I. C. Choong, J. A. Ellman, Combinatorial Target-Guided Ligand Assembly. Identification of Potent, Sub-type Selective c-Src Inhibitors , Proc. Natl. Acad. Sci, USA, 2000, 97, 2419-2424. 

Maly, D.J., Choong, I.C., Ellman, J.A. Combinatorial target-guided ligand assembly identification of potent subtype-selective c-Src inhibitors. 

Several of the new Bcr-Abl kinase inhibitors reported subsequent to imatinib also inhibit Src, a non-receptor tyrosine kinase. In 2000, il was re-porled lhat the known Src inhibitor PD180970 (12) also inhibited Abl kinase [73] (Scheme 5). This property was soon found to be shared by several other pyrido[2,3-d]pyrimidine Src inhibitors including PD173955 (13) [74] (Scheme 5). A crystal structure of PD 173955 demonstrated that this compound could bind to both the active and inactive form of Abl [37]. While the conformation of active Src kinase is similar to that of active Abl, the conformations of the inactive kinases are quite different. Unlike PD 173955, imatinib only binds the inactive form of Abl. The inability of imatinib to inhibit Src is... 

The initial pyrido[2,3-d]pyrimidines were first reported as Src inhibitors by Parke-Davis, now Pfizer, and the first disclosures of Abl activity were done in collaboration with academic researchers. Although the recent studies with these analogs were reported by academic groups, it has been stated that Sloan-Kettering is working with a pharmaceutical company to develop a compoimd from this class [92]. 

In 2004 Astra Zeneca published on a series of 4-anilinoquinazohnes as potent Src inhibitors [153]. One analog, AZM475271 (37), inhibited Src kinase activity with an IC50 of 10 nM, and had in vivo efficacy in a mouse model of pancreatic cancer [154] (Scheme 11). 

Figure 2.3 First HTS for the detection allosteric Src inhibitors. In the absence of ligand, acrylodan-labeled cSrc shows two emission maxima at 475 and 505 nm. Type I ligands induce a robust loss of fluorescence intensity (arrows) at 475 nm, resulting in a red shift in the emission maxima to 510 nm (right panel). Type II and III inhibitors stabilize the inactive kinase conformation and elicit a different response in which the emissions at 475 and 505 nm are equally reduced. The emission signal at 445 nm is less sensitive to ligand binding and serves as an internal reference point, allowing for...

A series of peptidic macrocycles has been published by researehers from Harvard and Stony Brook University who reported highly specific, bisubstrate-competitive proto-oncogene tyrosine protein kinase Src inhibitors... 

Though a large number of small molecule inhibitors against a variety of tyrosine kinases are being developed, the most advanced drugs can be roughly classified as (i) Bcr-Abl/Src family kinase inhibitors, (ii) ErbB inhibitors and (iii) broad spectrum TfCIs with an anti-angiogenic component. 

Furthermore, peptidomimetic SH2 domain inhibitors for Src, such as AP-22408 have been designed that interfere with effector binding and thereby disrupt signal transduction. AP-22408 decreases bone resorption in animal studies and may be a promising drug to treat osteoporosis and other bone diseases, such as Paget s disease and osteolytic bone metastasis. 

Several other inhibitors of nonreceptor PTKs are currently in development but only a few of them are studied in clinical trials. Noteworthy, Dasatinib does not only inhibit c-Abl, but also potently blocks Src activity, a property that may contribute to its beneficial clinical effects in CML. Other kinase inhibitors being developed that inhibit c-Abl and/or Src are AZD-0530, AP-23994, PD-0183805, SU-6656, and Bosutinib (SKI-606). Furthermore, peptidomimetic SH2 domain inhibitors for Src, such as AP-22408 have been designed that decrease bone resorption and may be promising drugs to treat osteoporosis and other bone diseases, such as Paget s disease and osteolytic bone metastasis. 

Luther M, Rusnak D, Sternbach DD, Mehrotra M, Peel M, Shampine L, Davis R, Robbins J, Patel IR, Kassel D, Burkhart W, Moyer M, Bradshaw T, Berman J. Peptide inhibitors of Src SH3-SH2-phosphoprotein interactions. J Biol Chem 1994 269 31711-31719. Also, for pTyr mimics see Ye B, Akamatsu M, Shoelson SE, Wolf G, Giorgetti-Peraldi S, Yan X, Roller PP, Burke TR Jr. L-0-(2-Malonyl)tyrosine a new phosphotyrosyl mimetic for the preparation of Src homology 2 domain inhibitory peptides. J Med Chem 1995 38 4270-4275. 

Bohacek RS, Dalgarmo DC, Hatada M, Jacobsen VA, Lynch BA, MacekKJ, Merry T, Metcalf CA III, Narula SS, Sawyer TK, Shakespeare WC, Violette SM, Weigele M. X-ray structure of citrate bound to Src SH2 leads to a high affinity, bone-targeted Src SH2 inhibitor. J Med Chem 2001 44 660-663. 

For recent papers describing the use of pTyr mimics in the context of Src and Lck SH2 inhibitors, see (a) Kawahata N, Yang MG, Luke GP, Shakespeare WC, Sundaramoorthi R, Wang Y, Johnson D, Merry T, Violette S, Guan W, Bartlett C, Smith J, Hatada M, Lu X, Dalgamo DC,... 

Dalgarno DC, Weigele M, Lesuisse D, Sawyer TK, Baron R. Bone-targeted Src SH2 inhibitors block Src cellular activity and osteoclast-mediated resorption. Bone 2001 28 54-64. 

---