Saracatinib Explained

Saracatinib (AZD-0530) is an experimental drug being developed by AstraZeneca. It acts as a dual kinase inhibitor, with selective actions as a Src inhibitor and a Bcr-Abl tyrosine-kinase inhibitor.^{[1] [2]}

It was originally under development for the treatment of cancer, but while it appeared promising in animal studies and was well tolerated in humans, it failed to show sufficient efficacy in cancer patients and was ultimately not developed further for this application. However, saracatinib has subsequently been researched for other applications such as Alzheimer's disease. AZD0530 is an inhibitor of Src and Abl family kinases1. It has been developed as treatment for malignancies because these kinases play a role in tumor invasion and proliferation. However, the Src family kinases (SFKs) are highly expressed in brain and have major effects on synaptic plasticity2. Moreover, the investigators have recently shown that a specific SFK, namely Fyn, is aberrantly activated by specific conformations of the Amyloid Beta (Aß) peptide from Alzheimer's disease (AD). Genetic deletion of Fyn rescues AD deficits in preclinical models. This clinical trial will test the potential benefit of AZD0530 for Alzheimer's disease modification.^{[3] [4] [5] [6]} and schizophrenia.^[7] It has furthermore been described that Saracatinib impairs maintenance of human T-cells Acute Lymphoblastic Leukemia by targeting the LCK tyrosine kinase in cells displaying high level of lipid rafts.^[8]

See also

• Bosutinib
• Dasatinib

Notes and References

1. Hennequin LF, Allen J, Breed J, Curwen J, Fennell M, Green TP, Lambert-van der Brempt C, Morgentin R, Norman RA, Olivier A, Otterbein L, Plé PA, Warin N, Costello G . 6 . 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 . Journal of Medicinal Chemistry . 49 . 22 . 6465–88 . November 2006 . 17064066 . 10.1021/jm060434q .
2. Schenone S, Brullo C, Musumeci F, Botta M . Novel dual Src/Abl inhibitors for hematologic and solid malignancies . Expert Opinion on Investigational Drugs . 19 . 8 . 931–45 . August 2010 . 20557276 . 10.1517/13543784.2010.499898 . 25831266 .
3. Patrick J. Loehrer . Gubens MA, Burns M, Perkins SM, Pedro-Salcedo MS, Althouse SK, Loehrer PJ, Wakelee HA . A phase II study of saracatinib (AZD0530), a Src inhibitor, administered orally daily to patients with advanced thymic malignancies . Lung Cancer . 89 . 1 . 57–60 . July 2015 . 26009269 . 10.1016/j.lungcan.2015.04.008 .
4. Reddy SM, Kopetz S, Morris J, Parikh N, Qiao W, Overman MJ, Fogelman D, Shureiqi I, Jacobs C, Malik Z, Jimenez CA, Wolff RA, Abbruzzese JL, Gallick G, Eng C . 6 . Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer . Investigational New Drugs . 33 . 4 . 977–84 . August 2015 . 26062928 . 10.1007/s10637-015-0257-z . 13450978 .
5. Kaufman AC, Salazar SV, Haas LT, Yang J, Kostylev MA, Jeng AT, Robinson SA, Gunther EC, van Dyck CH, Nygaard HB, Strittmatter SM . 6 . Fyn inhibition rescues established memory and synapse loss in Alzheimer mice . Annals of Neurology . 77 . 6 . 953–71 . June 2015 . 25707991 . 4447598 . 10.1002/ana.24394 .
6. Nygaard HB, Wagner AF, Bowen GS, Good SP, MacAvoy MG, Strittmatter KA, Kaufman AC, Rosenberg BJ, Sekine-Konno T, Varma P, Chen K, Koleske AJ, Reiman EM, Strittmatter SM, van Dyck CH . 6 . A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer's disease . Alzheimer's Research & Therapy . 7 . 1 . 35 . 25874001 . 4396171 . 10.1186/s13195-015-0119-0 . 2015 . free .
7. Web site: MICA: SRC inhibitors as potential antipsychotics: human testing with psilocybin. . Imperial College London . 27 July 2015 .
8. Buffière A, Accogli T, Saint-Paul L, Lucchi G, Uzan B, Ballerini P, Bastie JN, Delva L, Pflumio F, Quéré R . 6 . Saracatinib impairs maintenance of human T-ALL by targeting the LCK tyrosine kinase in cells displaying high level of lipid rafts . Leukemia . 32 . 9 . 2062–2065 . September 2018 . 29535432 . 10.1038/s41375-018-0081-5 . 3833020 .