Delving into the Latest Updates on Convert Pharmaceuticals SA with Synapse

Overview

Tags

Congenital Disorders

Neoplasms

Skin and Musculoskeletal Diseases

Small molecule drug

Disease domain score

A glimpse into the focused therapeutic areas

Technology Platform

Most used technologies in drug development

Targets

Most frequently developed targets

Disease Domain	Count

Neoplasms	1

Top 5 Drug Type	Count

Small molecule drug	1

Top 5 Target	Count

DNA	1

Author: Anderson, Robert F. ; Balbo, Silvia ; Theys, Jan ; Thiolloy, Sophie ; van der Wiel, Alexander M.A. ; Bull, Matthew R. ; Solivio, Morwena J. ; Marcus, Damiënne ; Patterson, Adam V. ; Guise, Christopher P. ; Lin, Xiaojing ; Ashoorzadeh, Amir ; Heyerick, Arne ; Dubois, Ludwig J. ; Mowday, Alexandra M. ; Jackson-Patel, Victoria ; Fu, Zhe ; Niemans, Raymon ; Liu, Emily ; Hicks, Kevin O. ; Lieuwes, Natasja G. ; Biemans, Rianne ; Yaromina, Ala ; Smaill, Jeff B. ; Kumara, Sisira ; Deschoemaeker, Sofie ; Abbattista, Maria R. ; Lambin, Philippe ; Jochems, Arthur

AbstractHypoxia-activated prodrugs (HAP) are a promising class of antineoplastic agents that can selectively eliminate hypoxic tumor cells. This study evaluates the hypoxia-selectivity and antitumor activity of CP-506, a DNA alkylating HAP with favorable pharmacologic properties. Stoichiometry of reduction, one-electron affinity, and back-oxidation rate of CP-506 were characterized by fast-reaction radiolytic methods with observed parameters fulfilling requirements for oxygen-sensitive bioactivation. Net reduction, metabolism, and cytotoxicity of CP-506 were maximally inhibited at oxygen concentrations above 1 μmol/L (0.1% O2). CP-506 demonstrated cytotoxicity selectively in hypoxic 2D and 3D cell cultures with normoxic/anoxic IC50 ratios up to 203. Complete resistance to aerobic (two-electron) metabolism by aldo-keto reductase 1C3 was confirmed through gain-of-function studies while retention of hypoxic (one-electron) bioactivation by various diflavin oxidoreductases was also demonstrated. In vivo, the antitumor effects of CP-506 were selective for hypoxic tumor cells and causally related to tumor oxygenation. CP-506 effectively decreased the hypoxic fraction and inhibited growth of a wide range of hypoxic xenografts. A multivariate regression analysis revealed baseline tumor hypoxia and in vitro sensitivity to CP-506 were significantly correlated with treatment response. Our results demonstrate that CP-506 selectively targets hypoxic tumor cells and has broad antitumor activity. Our data indicate that tumor hypoxia and cellular sensitivity to CP-506 are strong determinants of the antitumor effects of CP-506.

Selectively Targeting Tumor Hypoxia with the Hypoxia-Activated Prodrug CP-506

Author: Lin, Xiaojing ; Theys, Jan ; Jackson-Patel, Victoria ; Abbattista, Maria ; Patterson, Adam ; Lieuwes, Natasja ; Guise, Christopher ; Mowday, Alexandra ; Smaill, Jeff ; Fu, Zhe ; Marcus, Damiënne ; Heyerick, Arne ; Hicks, Kevin ; Thiolloy, Sophie ; Deschoemaeker, Sofie ; Niemans, Raymon ; Liu, Emily ; Wiel, Alexander M.A. van der ; Anderson, Robert ; Biemans, Rianne ; Yaromina, Ala ; Solivio, Morwena ; Ashoorzadeh, Amir ; Bull, Matthew ; Lambin, Philippe ; Kumara, Sisira ; Balbo, Silvia ; Dubois, Ludwig ; Jochems, Arthur

AbstractBackground Hypoxia-activated prodrugs (HAPs) are a promising class of antineoplastic agents that can selectively eliminate hypoxic tumor cells. The present study evaluates the hypoxia-selectivity and antitumor activity of CP-506, a DNA alkylating HAP with favorable pharmacological properties. Methods Stoichiometry of reduction, one-electron affinity, and back-oxidation rate of CP-506 were characterized by fast-reaction radiolytic methods. In vitro, 2D monolayer and 3D spheroid and multicellular layer cultures were used to investigate the hypoxia-selectivity of CP-506. In vivo, the causal relationship between tumor oxygenation and antitumor effects of CP-506 was assessed. Mice bearing a range of human tumor xenografts were exposed to CP-506 and tumor growth was monitored. A multivariate linear regression model was used to identify factors associated with CP-506 treatment outcome. Results Net reduction, metabolism, and cytotoxicity of CP-506 were maximally inhibited at oxygen concentrations above 1 µM (0.1% O2). CP-506 demonstrated cytotoxicity selectively in hypoxic 2D and 3D cell cultures with normoxic/anoxic IC50 ratios up to 203. In vivo, the antitumor effects of CP-506 were selective for hypoxic tumor cells and causally related to tumor oxygenation. CP-506 effectively decreased the hypoxic fraction and inhibited growth of a wide range of hypoxic xenografts. Two well-oxygenated models were refractory to treatment despite intrinsic anoxic sensitivity in vitro. A multivariate regression analysis revealed baseline tumor hypoxia and in vitro sensitivity to CP-506 to significantly correlate with treatment response. Conclusions Our results demonstrate that CP-506 selectively sterilizes hypoxic tumor cells and has broad antitumor activity. Our data also indicate that tumor hypoxia and cellular sensitivity to CP-506 are strong determinants of the antitumor effects of CP-506.

100 Deals associated with Convert Pharmaceuticals SA

Login to view more data

100 Translational Medicine associated with Convert Pharmaceuticals SA

Login to view more data

Corporation Tree

Boost your research with our corporation tree data.

login

or

view full example data

Boost your research with our corporation tree data.

Pipeline

Pipeline Snapshot as of 16 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

Preclinical

1

Login to view more data