Berzosertib

Berzosertib
Clinical data
ATC code	None;
Identifiers
	IUPAC name 3-[3-[4-(methylaminomethyl)phenyl]-5-isoxazolyl]-5-(4-propan-2-ylsulfonylphenyl)-2-pyrazinamine;
CAS Number	1232416-25-9;
PubChem CID	59472121;
DrugBank	DB11794;
ChemSpider	30773968;
UNII	L423PRV3V3;
KEGG	D11148;
ChEBI	CHEBI:131166;
CompTox Dashboard (EPA)	DTXSID601025940 ;
Chemical and physical data
Formula	C24H25N5O3S
Molar mass	463.56 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC(C)S(=O)(=O)C1=CC=C(C=C1)C2=CN=C(C(=N2)C3=CC(=NO3)C4=CC=C(C=C4)CNC)N;
	InChI InChI=1S/C24H25N5O3S/c1-15(2)33(30,31)19-10-8-18(9-11-19)21-14-27-24(25)23(28-21)22-12-20(29-32-22)17-6-4-16(5-7-17)13-26-3/h4-12,14-15,26H,13H2,1-3H3,(H2,25,27); Key:JZCWLJDSIRUGIN-UHFFFAOYSA-N;

Berzosertib (VE-822, VX-970, M6620) is a drug originally invented by Vertex Pharmaceuticals and licensed to Merck KGaA, Darmstadt, Germany, for development. It acts as a potent inhibitor of the enzyme ataxia telangiectasia and Rad3 related (ATR) and with lower potency as an inhibitor of ATM serine/threonine kinase (ATM). These enzymes are both involved in detecting DNA damage as part of cell cycle checkpoints during cell division. By inhibiting their activity, berzosertib interferes with the ability of rapidly dividing cells to detect damage to DNA, and this makes it useful as a potential treatment for some forms of cancer by causing accumulation of DNA damage in the cancer cells and thus reducing their viability. It has progressed furthest in trials for the treatment of ovarian cancer, though also shows activity against numerous other cancer types.^[1]^[2]^[3]

Phase 1 trial results show promising results in the first clinical trial of the drug class. The new study, designed to test the drug's safety, found that half of patients given the new drug either alone or with platinum chemotherapy saw their cancer stop growing, and two patients saw their tumors shrink or disappear completely.^[4]^[5]

In a UCLA-led study, berzosertib showed promise in treating COVID-19.^[6]

References

^ Karnitz LM, Zou L (November 2015). "Molecular Pathways: Targeting ATR in Cancer Therapy". Clinical Cancer Research. 21 (21): 4780–5. doi:10.1158/1078-0432.CCR-15-0479. PMC 4631635. PMID 26362996.
^ Lecona E, Fernandez-Capetillo O (September 2018). "Targeting ATR in cancer". Nature Reviews. Cancer. 18 (9): 586–595. doi:10.1038/s41568-018-0034-3. PMID 29899559. S2CID 49189972.
^ Gorecki L, Andrs M, Rezacova M, Korabecny J (June 2020). "Discovery of ATR kinase inhibitor berzosertib (VX-970, M6620): Clinical candidate for cancer therapy". Pharmacology & Therapeutics. 210: 107518. doi:10.1016/j.pharmthera.2020.107518. PMID 32109490. S2CID 211564796.
^ "New Class of Precision Medicine Strips Cancer of its DNA Defenses". www.laboratoryequipment.com. 23 June 2020. Retrieved 2020-06-24.
^ Konstantinopoulos PA, Cheng SC, Wahner Hendrickson AE, Penson RT, Schumer ST, Doyle LA, et al. (July 2020). "Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial". The Lancet. Oncology. 21 (7): 957–968. doi:10.1016/S1470-2045(20)30180-7. PMC 8023719. PMID 32553118.
^ Goddard, Jack (25 March 2021). "Merck and UCLA find new COVID-19 treatment candidate". Pharmafile. Retrieved 2021-05-01.

[pmid26362996-1] Karnitz LM, Zou L (November 2015). "Molecular Pathways: Targeting ATR in Cancer Therapy". Clinical Cancer Research. 21 (21): 4780–5. doi:10.1158/1078-0432.CCR-15-0479. PMC 4631635. PMID 26362996.

[pmid29899559-2] Lecona E, Fernandez-Capetillo O (September 2018). "Targeting ATR in cancer". Nature Reviews. Cancer. 18 (9): 586–595. doi:10.1038/s41568-018-0034-3. PMID 29899559. S2CID 49189972.

[pmid32109490-3] Gorecki L, Andrs M, Rezacova M, Korabecny J (June 2020). "Discovery of ATR kinase inhibitor berzosertib (VX-970, M6620): Clinical candidate for cancer therapy". Pharmacology & Therapeutics. 210: 107518. doi:10.1016/j.pharmthera.2020.107518. PMID 32109490. S2CID 211564796.

[4] "New Class of Precision Medicine Strips Cancer of its DNA Defenses". www.laboratoryequipment.com. 23 June 2020. Retrieved 2020-06-24.

[pmid32553118-5] Konstantinopoulos PA, Cheng SC, Wahner Hendrickson AE, Penson RT, Schumer ST, Doyle LA, et al. (July 2020). "Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial". The Lancet. Oncology. 21 (7): 957–968. doi:10.1016/S1470-2045(20)30180-7. PMC 8023719. PMID 32553118.

[6] Goddard, Jack (25 March 2021). "Merck and UCLA find new COVID-19 treatment candidate". Pharmafile. Retrieved 2021-05-01.

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