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Identification of allosteric inhibitors of the ecto-5'-nucleotidase (CD73) targeting the dimer interface
Rahila Rahimova1, Simon Fontanel2, Corinne Lionne3
1Institut de Recherche en Infectiologie de Montpellier (IRIM), Univ. Montpellier, CNRS, Montpellier, France; Institut de Biologie Computationnelle (IBC), Montpellier, France.
Abstract:
The ecto-5'-nucleotidase CD73 plays an important role in the production of immune-suppressive adenosine in tumor micro-environment, and has become a validated drug target in oncology. Indeed, the anticancer immune response involves extracellular ATP to block cell proliferation through T-cell activation. However, in the tumor micro-environment, two extracellular membrane-bound enzymes (CD39 and CD73) are overexpressed and hydrolyze efficiently ATP into AMP then further into immune-suppressive adenosine. To circumvent the impact of CD73-generated adenosine, we applied an original bioinformatics approach to identify new allosteric inhibitors targeting the dimerization interface of CD73, which should impair the large dynamic motions required for its enzymatic function. Several hit compounds issued from virtual screening campaigns showed a potent inhibition of recombinant CD73 with inhibition constants in the low micromolar range and exhibited a non-competitive inhibition mode. The structure-activity relationships studies indicated that several amino acid residues (D366, H456, K471, Y484 and E543 for polar interactions and G453-454, I455, H456, L475, V542 and G544 for hydrophobic contacts) located at the dimerization interface are involved in the tight binding of hit compounds and likely contributed for their inhibitory activity. Overall, the gathered information will guide the upcoming lead optimization phase that may lead to potent and selective CD73 inhibitors, able to restore the anticancer immune response.
Insights
Researchers identified novel allosteric inhibitors for ecto-5'-nucleotidase CD73, a key target in oncology. These compounds block immune suppression in the tumor microenvironment, potentially restoring anticancer immune responses.
Area of Science:
- Oncology
- Biochemistry
- Immunology
Background:
- Ecto-5 '-nucleotidase CD73 is crucial for generating immune-suppressive adenosine in the tumor microenvironment.
- Overexpressed CD73 and CD39 enzymes hydrolyze extracellular ATP, promoting adenosine production and hindering anti-cancer immunity.
- CD73 is a validated drug target for restoring anti-cancer immune responses.
Purpose of the Study:
- To identify novel allosteric inhibitors of CD73 by targeting its dimerization interface.
- To develop compounds that impair CD73's enzymatic function and reduce immune suppression.
- To guide lead optimization for potent and selective CD73 inhibitors.
Main Methods:
- Applied a bioinformatics approach for virtual screening to identify CD73 inhibitors.
- Conducted biochemical assays to determine inhibition constants and mode of action.
- Performed structure-activity relationship studies to understand compound binding interactions.
Main Results:
- Identified several hit compounds with potent inhibition of recombinant CD73 (low micromolar range).
- Observed a non-competitive inhibition mode for the identified compounds.
- Characterized key amino acid residues at the dimerization interface involved in compound binding.
Conclusions:
- The identified allosteric inhibitors show promise for targeting CD73.
- Understanding the structure-activity relationships facilitates lead optimization.
- These inhibitors have the potential to restore anti-cancer immune responses by modulating the tumor microenvironment.