Saracatinib

Saracatinib
Clinical data
Routes of; administration	Oral
Legal status
Legal status	Investigational;
Identifiers
	IUPAC name N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methyl-1-piperazinyl)ethoxy]-5-[(tetrahydro-2H-pyran-4-yl)oxy]-4-quinazolinamine;
CAS Number	379231-04-6;
PubChem CID	10302451;
ChemSpider	8477917;
UNII	9KD24QGH76;
KEGG	D09664;
CompTox Dashboard (EPA)	DTXSID90191355 ;
Chemical and physical data
Formula	C27H32ClN5O5
Molar mass	542.03 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C4CN(C)CCN4CCOc(cc2ncn3)cc(OC6CCOCC6)c2c3Nc1c(Cl)ccc5OCOc15;
	InChI InChI=1S/C27H32ClN5O5/c1-32-6-8-33(9-7-32)10-13-35-19-14-21-24(23(15-19)38-18-4-11-34-12-5-18)27(30-16-29-21)31-25-20(28)2-3-22-26(25)37-17-36-22/h2-3,14-16,18H,4-13,17H2,1H3,(H,29,30,31); Key:OUKYUETWWIPKQR-UHFFFAOYSA-N;

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]

References

^ Hennequin LF, Allen J, Breed J, Curwen J, Fennell M, Green TP, et al. (November 2006). "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. doi:10.1021/jm060434q. PMID 17064066.
^ Schenone S, Brullo C, Musumeci F, Botta M (August 2010). "Novel dual Src/Abl inhibitors for hematologic and solid malignancies". Expert Opinion on Investigational Drugs. 19 (8): 931–45. doi:10.1517/13543784.2010.499898. PMID 20557276.
^ Gubens MA, Burns M, Perkins SM, Pedro-Salcedo MS, Althouse SK, Loehrer PJ, Wakelee HA (July 2015). "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. doi:10.1016/j.lungcan.2015.04.008. PMID 26009269.
^ Reddy SM, Kopetz S, Morris J, Parikh N, Qiao W, Overman MJ, et al. (August 2015). "Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer". Investigational New Drugs. 33 (4): 977–84. doi:10.1007/s10637-015-0257-z. PMID 26062928.
^ Kaufman AC, Salazar SV, Haas LT, Yang J, Kostylev MA, Jeng AT, et al. (June 2015). "Fyn inhibition rescues established memory and synapse loss in Alzheimer mice". Annals of Neurology. 77 (6): 953–71. doi:10.1002/ana.24394. PMC 4447598. PMID 25707991.
^ Nygaard HB, Wagner AF, Bowen GS, Good SP, MacAvoy MG, Strittmatter KA, et al. (2015). "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. doi:10.1186/s13195-015-0119-0. PMC 4396171. PMID 25874001.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ "MICA: SRC inhibitors as potential antipsychotics: human testing with psilocybin". Imperial College London. 27 July 2015.
^ Buffière A, Accogli T, Saint-Paul L, Lucchi G, Uzan B, Ballerini P, et al. (September 2018). "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. doi:10.1038/s41375-018-0081-5. PMID 29535432.

[1] Hennequin LF, Allen J, Breed J, Curwen J, Fennell M, Green TP, et al. (November 2006). "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. doi:10.1021/jm060434q. PMID 17064066.

[2] Schenone S, Brullo C, Musumeci F, Botta M (August 2010). "Novel dual Src/Abl inhibitors for hematologic and solid malignancies". Expert Opinion on Investigational Drugs. 19 (8): 931–45. doi:10.1517/13543784.2010.499898. PMID 20557276.

[3] Gubens MA, Burns M, Perkins SM, Pedro-Salcedo MS, Althouse SK, Loehrer PJ, Wakelee HA (July 2015). "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. doi:10.1016/j.lungcan.2015.04.008. PMID 26009269.

[4] Reddy SM, Kopetz S, Morris J, Parikh N, Qiao W, Overman MJ, et al. (August 2015). "Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer". Investigational New Drugs. 33 (4): 977–84. doi:10.1007/s10637-015-0257-z. PMID 26062928.

[5] Kaufman AC, Salazar SV, Haas LT, Yang J, Kostylev MA, Jeng AT, et al. (June 2015). "Fyn inhibition rescues established memory and synapse loss in Alzheimer mice". Annals of Neurology. 77 (6): 953–71. doi:10.1002/ana.24394. PMC 4447598. PMID 25707991.

[6] Nygaard HB, Wagner AF, Bowen GS, Good SP, MacAvoy MG, Strittmatter KA, et al. (2015). "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. doi:10.1186/s13195-015-0119-0. PMC 4396171. PMID 25874001.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[7] "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, et al. (September 2018). "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. doi:10.1038/s41375-018-0081-5. PMID 29535432.

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See also

References