Plocabulin ( PM184 ) Empieza a Posicionarse en la I+D+i Internacional . PharmaMar Tiene 5 Fármacos en Ensayos Clínicos : Yondelis, Aplidin, ZepZelCa, Plocabulin y PM-14 . Tres de Ellos Ya en el Mercado .

Interdimeric Curvature in Tubulin–Tubulin Complexes Delineates the Microtubule-Destabilizing Properties of Plocabulin .

Karen R. Navarrete and Verónica. A. Jiménez .

Publication Date : July 20, 2020 .

Copyright © 2020 American Chemical Society .

Abstract

Plocabulin is a Novel Microtubule (MT) destabilizer agent with potent antineoplastic activity. This compound binds to the maytansine site at the longitudinal interface between tubulin dimers and exerts a hinge-like effect that disrupts normal microtubule assembly. 

Plocabulin has emerged as a valuable model for the rational design of novel MT destabilizers because of its unique structural and mechanistic features. 

To make progress on this matter, detailed molecular-level understanding of the ligand–protein interactions responsible for Plocabulin association and the conformation and energetic effects arising from Plocabulin binding on the longitudinal interaction between tubulin dimers must be provided.

 In this work, fully atomistic MD simulations and MM/GBSA binding free-energy calculations were used to examine the association of plocabulin to one or two tubulin dimers in longitudinal arrangement.

 Our results revealed that Plocabulin binding is favored by the addition of a second tubulin dimer and that this ligand promotes the assembly of curved tetrameric arrangements with strengthened longitudinal interdimeric interactions compared to ligand-free systems. 

The Applicability of these findings to the rational discovery of novel MT destabilizers was tested using MD and MM/GBSA calculations as filtering tools to narrow the results of virtual screening among an FDA-approved drug database. 

Our Results Confirmed that tight-binding ligands do not necessarily exert the expected conformational and energetic effects on longitudinal tubulin–tubulin interactions, which is a matter to consider in future design strategies.

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P.J. : Plocabulin ( PM184 ) es un Inhibidor de Microtúbulos que Ejerce su Efecto Mediante un Nuevo Mecanismo de Interacción con Microtúbulos. El Compuesto Inhibe el Crecimiento de las Células tumorales Bloqueando su Ciclo Celular al Interferir con el Proceso de Mitosis.

ZepZelCa TM ( Lurbinectedin ) : First Approval in EEUU ... The Australian Therapeutic Goods Administration, Are Collabora on The Review of ZepZelCa Under The Project Orbis Initiative .

*.- Australia ( TGA ) Has Granted Provisional Designation for New Drug Lurbinectedin based on Encouraging Phase 2 Results and High Unmet Medical Need

*.- ZepZelCa TM To Be Considered Under the 'Project Orbis' Initiative, Which has Been Designed to Allow Collaboration Between the FDA and Select Internacional Regulators, Including the TGA .

*.- ZepZelCa TM Currently Available to Patients in Australia and Singapore Vía a Named Co-pay Patient Access Program .

Anthony Markham / Published: 20 August 2020

Abstract

The Oncogenic Transcription Inhibitor Lurbinectedin (ZEPZELCA™) is Being Developed by PharmaMar as a Treatment for Various Cáncers.

The Drug has Been Granted Orphan Drug Status for the Treatment of Small CELL Lung cancer (SCLC) by Regulatory Authorities in Múltiple Countries Worldwide and was Approved in the USA in June 2020 for the Treatment of Adult Patients with Metastatic SCLC with disease Progression on or After Platinum-based Chemotherapy.

The US FDA and Internacional Regulators, Including the Australian Therapeutic Goods Administration, are Collaborating on the Review of Lurbinectedin under the Project Orbis Initiative.

Clinical Investigation in Other Solid Cáncers is Ongoing. This Article Summarizes the Milestones in the Development of Lurbinectedin Leading to This First Approval for the Treatment of Metastatic SCLC.

El artículo Completo es de Pago ... 41,55 euros .