Sabizabulin Explained

Sabizabulin is a chemical compound from the group of indole and imidazole derivatives that was first reported in 2012 by Dalton, Li, and Miller.[1] It is being studied as a mitotic inhibitor and chemotherapeutic agent in castration-resistant metastatic prostate cancer[2] and in SARS-CoV-2 (COVID-19) infections.[3]

Properties

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.[4] 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.[5]

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.

Research

COVID-19 therapy

In a phase III study on the treatment of severe courses of COVID-19,[6] [7] sabizabulin reduced mortality by 55% according to the manufacturer.[8] 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.[9] [10]

Further reading

Notes and References

  1. Li . Chien-Ming . Lu . Yan . Chen . Jianjun . Costello . Terrence A. . Narayanan . Ramesh . Dalton . Mara N. . Snyder . Linda M. . Ahn . Sunjoo . Li . Wei . Miller . Duane D. . Dalton . James T. . 2012-07-04 . Orally Bioavailable Tubulin Antagonists for Paclitaxel-Refractory Cancer . Pharmaceutical Research . 29 . 11 . 3053–3063 . 10.1007/s11095-012-0814-5 . 22760659 . 3646298 . 0724-8741.
  2. Markowski MC, Tutrone R, Pieczonka C, Barnette KG, Getzenberg RH, Rodriguez D, Steiner MS, Saltzstein DR, Eisenberger MA, Antonarakis ES . A Phase 1b/2 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. OF1–OF7. April 2022 . 35416959 . 10.1158/1078-0432.CCR-22-0162 . 9774054 . 248128050 .
  3. Web site: COVID-19: Krebsmittel Sabizabulin halbiert Sterberate bei schweren Erkrankungen. aerzteblatt.de. 2022-04-14. rme. 13 April 2022.
  4. Web site: Sabizabulin for Breast Cancer . 2022-05-17 . Veru Inc. . en-US.
  5. Web site: Sabizabulin (Code C158517) . 2022-04-14 . NCI Thesaurus.
  6. 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 . 13 April 2021 . 1 May 2022.
  7. Web site: 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 . 1 May 2022 . 1 May 2022 . https://web.archive.org/web/20220501173559/https://verupharma.gcs-web.com/news-releases/news-release-details/veru-enrolls-first-patient-phase-3-clinical-trial-sabizabulin . dead .
  8. 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. . 11 April 2022 . 30 April 2022 . 16 April 2022 . https://web.archive.org/web/20220416004327/https://verupharma.gcs-web.com/news-releases/news-release-details/verus-novel-covid-19-drug-candidate-reduces-deaths-55 . dead .
  9. News: Rabin . Roni . New Drug Slashed Deaths Among Patients With Severe Covid, Maker Claims . 21 April 2022 . The New York Times . 11 Apr 2022.
  10. 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 . Veru Inc. . GlobeNewswire . 25 April 2022 . 30 April 2022.

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