posted on 2021-01-05, 13:43authored byEhesan U. Sharif, Jaroslaw Kalisiak, Kenneth V. Lawson, Dillon H. Miles, Eric Newcomb, Erick A. Lindsey, Brandon R. Rosen, Laurent P. P. Debien, Ada Chen, Xiaoning Zhao, Stephen W. Young, Nigel P. Walker, Norbert Sträter, Emma R. Scaletti, Lixia Jin, Guifen Xu, Manmohan R. Leleti, Jay P. Powers
Solid tumors are often associated
with high levels of extracellular
ATP. Ectonucleotidases catalyze the sequential hydrolysis of ATP to
adenosine, which potently suppresses T-cell and NK-cell functions
via the adenosine receptors (A2a and A2b). The
ectonucleotidase CD73 catalyzes the conversion of AMP to adenosine.
Thus, increased CD73 enzymatic activity in the tumor microenvironment
is a potential mechanism for tumor immune evasion and has been associated
with poor prognosis in the clinic. CD73 inhibition is anticipated
to restore immune function by skirting this major mechanism of adenosine
generation. We have developed a series of potent and selective methylenephosphonic
acid CD73 inhibitors via a structure-based design. Key binding interactions
of the known inhibitor adenosine-5′-(α,β-methylene)diphosphate
(AMPCP) with hCD73 provided the foundation for our early designs.
The structure–activity relationship study guided by this structure-based
design led to the discovery of 4a, which exhibits excellent
potency against CD73, exquisite selectivity against related ectonucleotidases,
and a favorable pharmacokinetic profile.