Targeting PUMA/Bcl-xL interaction by new specific compounds to unleash apoptotic process in cancer cells

Appala Venkata Ramana Murthy; Vennu Narendar; Nangunoori Sampath Kumar; Pasula Aparna; Anagani Kanaka Durga Bhavani; Fabien Gautier; Sophie Barillé-Nion; Philippe Juin; Paul Mosset; René Grée; Nicolas Levoin

doi:10.1016/j.ejmech.2018.10.069

Targeting PUMA/Bcl-xL interaction by new specific compounds to unleash apoptotic process in cancer cells

Eur J Med Chem. 2019 Jan 15:162:334-347. doi: 10.1016/j.ejmech.2018.10.069. Epub 2018 Nov 2.

Affiliations

¹ Chemveda Life Sciences India Pvt. Ltd, #B-11/1, IDA Uppal, Hyderabad, 500039, Telangana, India; Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, 500 085, Telangana, India.
² Chemveda Life Sciences India Pvt. Ltd, #B-11/1, IDA Uppal, Hyderabad, 500039, Telangana, India.
³ Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, 500 085, Telangana, India.
⁴ Osmania University, Department of Chemistry, Hyderabad, 500007, Telangana, India. Electronic address: [email protected].
⁵ UMR 892 INSERM /6299 CNRS / Université de Nantes, Team 8 "Cell Survival and Tumor Escape in Breast Cancer", Institut de Recherche Thérapeutique de l'Université de Nantes, 8 quai Moncousu, BP 70721, 44007, Nantes Cedex 1, France; Institut de Cancérologie de l'Ouest, Centre de Lutte Contre le Cancer René Gauducheau, Boulevard Jacques Monod, 44805, Saint Herblain-Nantes Cedex, France; Plateforme IMPACT(®), Biogenouest Institut de Recherche Thérapeutique de l'Université de Nantes, 8, quai Moncousu, BP 70721 44007, Nantes Cedex 1, France.
⁶ UMR 892 INSERM /6299 CNRS / Université de Nantes, Team 8 "Cell Survival and Tumor Escape in Breast Cancer", Institut de Recherche Thérapeutique de l'Université de Nantes, 8 quai Moncousu, BP 70721, 44007, Nantes Cedex 1, France.
⁷ Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes), UMR 6226, F-35000, Rennes, France.
⁸ Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes), UMR 6226, F-35000, Rennes, France. Electronic address: [email protected].
⁹ Bioprojet-Biotech, 4 rue du Chesnay Beauregard, BP 96205, 35762, Saint Grégoire, France. Electronic address: [email protected].

PMID: 30453244
DOI: 10.1016/j.ejmech.2018.10.069

Abstract

We describe the first examples of small molecules able to disrupt the nanomolar interaction between the pro-apoptotic protein PUMA and its anti-apoptotic counterpart BcL-xL in malignant cells. Based on molecular modelling studies, we propose a rationale to this result, through a new "bottle-opener"-type strategy which could be of general use in the area of protein-protein interaction studies.

Keywords: BRET; Bcl-xL; Cancer; Molecular modelling; PUMA; Protein-protein interactions.

MeSH terms

Animals
Apoptosis / drug effects
Apoptosis Regulatory Proteins / metabolism*
Humans
Models, Molecular*
Neoplasms / drug therapy
Neoplasms / pathology
Protein Interaction Domains and Motifs / drug effects
Proto-Oncogene Proteins / metabolism*
bcl-X Protein / metabolism*

Substances

Apoptosis Regulatory Proteins
BBC3 protein, human
BCL2L1 protein, human
Proto-Oncogene Proteins
bcl-X Protein