Sunitinib

Structural formula
General
Non-proprietary name	Sunitinib
other names	N - [2- (diethylamino) ethyl] -5 - [( Z ) - (5-fluoro-1,2-dihydro-2-oxo-3 H -indol-3-ylidene) methyl] -2,4- dimethyl-1 H -pyrrole-3-carboxamide ( IUPAC )
Molecular formula	C 22 H 27 FN 4 O 2
External identifiers / databases
PubChem	5329102
ChemSpider	4486264
DrugBank	DB01268
Wikidata	Q417542
Drug information
ATC code	L01 XE04
Drug class	Tyrosine kinase inhibitor
properties
Molar mass	398.48 g mol −1
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS hazard labeling ; no classification available
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Sunitinib (trade name: Sutent ^® , manufactured by Pfizer ) is a receptor tyrosine kinase - inhibitor , which as a drug is approved to treat adult patients with unresectable and / or metastatic malignant gastrointestinal stromal tumors (GIST), when treatment with imatinib due to resistance or intolerance failed. The drug is also approved for the treatment of adults with advanced and / or metastatic renal cell carcinoma (RCC) and for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET) with disease progression in adults. In off-label use , sunitinib has been used with some success (increased survival) in patients with advanced choroidal melanoma .

background

The development of the active ingredient goes back to basic research by employees of the German Max Planck Institute for Biochemistry in collaboration with partner institutions in the USA in the 1980s. A company spun off in 1991 brought the results to commercial exploitation, was soon taken over and finally ended up at Pfizer in 2003. In 2006 the group succeeded in obtaining approval for the drug.

pharmacology

Sunitinib is an inhibitor of various receptor tyrosine kinases . These include PDGFR , VEGFR , c-Kit , FLT, CSF and RET . These receptors have been linked to tumor growth, pathological angiogenesis, and the development of metastases in cancer.

During the treatment with sunitinib the undesirable effects of fatigue, diarrhea, hand-foot syndrome , oral mucosal inflammation and arterial hypertension may occur. An underactive thyroid is often found to be the cause of fatigue, the cause of which is considered to be a reduced iodine uptake in the thyroid - presumably due to a non-competitive inhibition of thyroid peroxidase .

literature

L. Sun, C. Liang, S. Shirazian, Y. Zhou, T. Miller, J. Cui, JY Fukuda, J. Chu, A. Nematella, X. Wang, H. Chen: Discovery of 5- [5- fluoro-2-oxo-1,2-dihydroindole- (3Z) -ylidenemethyl] -2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet -derived growth factor receptor tyrosine kinase. In: J. Med. Chem. 46, 2003, pp. 1116-1119. (Synthesis)
NEJM: Méjean A, et al .: Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma . In: The New England Journal of Medicine . June 3, 2018, doi : 10.1056 / NEJMoa1803675 .
NEJM: Motzer R, et al .: Cytoreductive Nephrectomy - Patient Selection Is Key . In: The New England Journal of Medicine . June 3, 2018, doi : 10.1056 / NEJMe1806331 .

Individual evidence

↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
↑ European Medicines Agency: Sutent Product Information (EMEA / H / C / 000687 -II / 0038) (PDF; 841 kB).
Jump up ↑ Valsecci ME, Orloff M, Sato R, Chervoneva I, Shields C, Shields J, Mastrangelo M, Sato T: Adjuvant Sunitinib in High-Risk Patients with Uveal Melanoma. Ophthalmology 2017, published online September 18
↑ Press release MPI, February 8, 2006
^ Brian I. Rini, Ila Tamaskar, Phillip Shaheen, Renee Salas, Jorge Garcia, Laura Wood, Sethu Reddy, Robert Dreicer, Ronald M. Bukowski: Hypothyroidism in Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib. In: Journal of the National Cancer Institute . 99 (1), 2007, pp. 81-83; doi: 10.1093 / jnci / djk008 .
^ ^A ^b E. Wong, LS Rosen, M. Mulay, A. Vanvugt, M. Dinolfo, C. Tomoda, M. Sugawara, JM Hershman: Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. In: Thyroid. 17 (4), Apr 2007, pp. 351-355. PMID 17465866 .
↑ D. Mannavola, P. Coco, G. Vannucchi, R. Bertuelli, M. Carletto, PG Casali, P. Beck-Peccoz, L. Fugazzola: A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. In: J Clin Endocrinol Metab . 92 (9), Sep 2007, pp. 3531-3534. Epub 2007 Jun 26. PMID 17595247 .

[NV-1] This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.

[2] European Medicines Agency: Sutent Product Information (EMEA / H / C / 000687 -II / 0038) (PDF; 841 kB).

[3] Jump up ↑ Valsecci ME, Orloff M, Sato R, Chervoneva I, Shields C, Shields J, Mastrangelo M, Sato T: Adjuvant Sunitinib in High-Risk Patients with Uveal Melanoma. Ophthalmology 2017, published online September 18

[4] Press release MPI, February 8, 2006

[5] Brian I. Rini, Ila Tamaskar, Phillip Shaheen, Renee Salas, Jorge Garcia, Laura Wood, Sethu Reddy, Robert Dreicer, Ronald M. Bukowski: Hypothyroidism in Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib. In: Journal of the National Cancer Institute . 99 (1), 2007, pp. 81-83; doi: 10.1093 / jnci / djk008 .

[Wong-6] A ^b E. Wong, LS Rosen, M. Mulay, A. Vanvugt, M. Dinolfo, C. Tomoda, M. Sugawara, JM Hershman: Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. In: Thyroid. 17 (4), Apr 2007, pp. 351-355. PMID 17465866 .

[7] D. Mannavola, P. Coco, G. Vannucchi, R. Bertuelli, M. Carletto, PG Casali, P. Beck-Peccoz, L. Fugazzola: A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. In: J Clin Endocrinol Metab . 92 (9), Sep 2007, pp. 3531-3534. Epub 2007 Jun 26. PMID 17595247 .