Sabizabulin

Sabizabulin

Clinical data
Other names	VERU-111 [1] [2] [3]
Identifiers
IUPAC name [2-(1H-indol-3-yl)-1H-imidazol-5-yl]-(3,4,5-trimethoxyphenyl)methanone
CAS Number	1332881-26-1
PubChem CID	53379371
ChemSpider	28642581
UNII	37L1JX37J5
KEGG	D12519
ChEMBL	ChEMBL2163631
Chemical and physical data
Formula	C21H19N3O4
Molar mass	377.400 g·mol−1
3D model (JSmol)	Interactive image
SMILES COC1=CC(=CC(=C1OC)OC)C(=O)C2=CN=C(N2)C3=CNC4=CC=CC=C43
InChI InChI=1S/C21H19N3O4/c1-26-17-8-12(9-18(27-2)20(17)28-3)19(25)16-11-23-21(24-16)14-10-22-15-7-5-4-6-13(14)15/h4-11,22H,1-3H3,(H,23,24) Key:WQGVHOVEXMOLOK-UHFFFAOYSA-N

Sabizabulin is an investigational new drug that is being evaluated for the treatment of castration-resistant prostate cancer ^[4] and in SARS-CoV-2 (COVID-19) infections. ^[5] It is a tubulin polymerization inhibitor. ^{[6] [7]}

Sabizabulin is chemical compound from the group of indole and imidazole derivatives that was first reported in 2012 by Dalton, Li, and Miller. ^[8]

Pharmacology

Pharmacokinetics

Sabizabulin is not a substrate of P-glycoprotein (Pgp), an efflux pump that, when overexpressed, can confer resistance to taxanes, a group of widely used cancer therapeutics.

Mechanism of action

Sabizabulin, as an orally available molecule, acts on microtubules, a component of the cytoskeleton. It binds to the colchicine binding site on the beta subunit of tubulin, as well as a novel site on the alpha subunit, and causes both to crosslink, thus depolymerizing microtubules and preventing their polymerization. ^[9] By preventing mitotic spindle formation, this directly inhibits mitosis of tumor cells and endothelial cells attempting to form new blood vessels to feed them. In parallel, microtubule-mediated trafficking of cellular components (including androgen receptors into the nucleus), thus, a potential anti-androgen agent. The transport of viral particles (including SARS-CoV-2) may also be inhibited. These activities can inhibit viral replication and assembly. Inhibition of tubulin polymerization can also inhibit the release of pro-inflammatory cytokines and disrupt the activities of inflammatory cells. ^[10]

Research

COVID-19 therapy

In a phase III study on the treatment of severe courses of COVID-19, ^{[3] [11]} sabizabulin reduced mortality by 55% according to the manufacturer. ^[12] Because of the high efficacy, the test phase was stopped prematurely so that the drug no longer had to be withheld from the placebo control group. ^{[13] [14] [ medical citation needed ]}

References

1. "Substance Name: Sabizabulin". ChemIDplus. Retrieved 1 May 2022.
2. "Sabizabulin for COVID-19". Veru Inc. 14 January 2022. Retrieved 1 May 2022.
3. "VERU-111 in the Treatment of SARS-Cov-2 Infection by Assessing Its Effect on the Proportion of Patients Who Die on Study". ClinicalTrials.gov (Press release). 13 April 2021. Retrieved 1 May 2022.
4. Markowski MC, Tutrone R, Pieczonka C, Barnette KG, Getzenberg RH, Rodriguez D, et al. (July 2022). "A Phase Ib/II Study of Sabizabulin, a Novel Oral Cytoskeleton Disruptor, in Men with Metastatic Castration-resistant Prostate Cancer with Progression on an Androgen Receptor-targeting Agent". Clinical Cancer Research. 28 (13): 2789–2795. doi:10.1158/1078-0432.CCR-22-0162. PMC   9774054 . PMID   35416959. S2CID   248128050.
5. rme (13 April 2022). "COVID-19: Krebsmittel Sabizabulin halbiert Sterberate bei schweren Erkrankungen" [COVID-19: Cancer drug Sabizabulin halves death rate in severe cases]. aerzteblatt.de . Retrieved 14 April 2022.
6. "Sabizabulin - Veru Healthcare". AdisInsight. Springer Nature Switzerland AG.
7. Mahmud F, Deng S, Chen H, Miller DD, Li W (December 2020). "Orally available tubulin inhibitor VERU-111 enhances antitumor efficacy in paclitaxel-resistant lung cancer". Cancer Letters. 495: 76–88. doi:10.1016/j.canlet.2020.09.004. PMC   7669640 . PMID   32920198.
8. Li CM, Lu Y, Chen J, Costello TA, Narayanan R, Dalton MN, et al. (November 2012). "Orally bioavailable tubulin antagonists for paclitaxel-refractory cancer". Pharmaceutical Research. 29 (11): 3053–3063. doi:10.1007/s11095-012-0814-5. PMC   3646298 . PMID   22760659.
9. "Sabizabulin for Breast Cancer". Veru Inc. Retrieved 17 May 2022.
10. "Sabizabulin". NCI Thesaurus. U.S. National Cancer Institute. Code C158517. Retrieved 14 April 2022.
11. "Veru Enrolls First Patient in Phase 3 Clinical Trial of Sabizabulin (VERU-111) in High Risk Hospitalized COVID-19 Patients". Veru Inc. 19 May 2021. Archived from the original on 1 May 2022. Retrieved 1 May 2022.
12. "Veru's Novel COVID-19 Drug Candidate Reduces Deaths by 55% in Hospitalized Patients in Interim Analysis of Phase 3 Study; Independent Data Monitoring Committee Halts Study Early for Overwhelming Efficacy". Veru Inc. (Press release). 11 April 2022. Archived from the original on 16 April 2022. Retrieved 30 April 2022.
13. Rabin R (11 April 2022). "New Drug Slashed Deaths Among Patients With Severe Covid, Maker Claims". The New York Times. Retrieved 21 April 2022.
14. "Veru Announces Oral Late-Breaking Presentation of Phase 2 Data of Sabizabulin for the Treatment of Hospitalized Severe COVID-19 Patients at High Risk for Acute Respiratory Distress Syndrome at the 32nd European Congress of Clinical Microbiology & Infectious Diseases" (Press release). Veru Inc. 25 April 2022. Retrieved 30 April 2022– via GlobeNewswire.

Further reading

• Deng S, Krutilina RI, Wang Q, Lin Z, Parke DN, Playa HC, et al. (February 2020). "An Orally Available Tubulin Inhibitor, VERU-111, Suppresses Triple-Negative Breast Cancer Tumor Growth and Metastasis and Bypasses Taxane Resistance". Molecular Cancer Therapeutics. 19 (2): 348–363. doi:10.1158/1535-7163.MCT-19-0536. PMC   7007836 . PMID   31645441.
• Shahnoor S, Khan AM, Habiba U (June 2023). "Sabizabulin - an unprecedented yet effective drug against COVID-19". The Journal of the Pakistan Medical Association. 73 (6): 1363. doi: 10.47391/JPMA.7539 . PMID   37427659.