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Enzalutamide and Apalutamide: In Vitro Chemical Reactivity Studies and Activity in a Mouse Drug Allergy Model
journal contribution
posted on 2019-10-08, 21:17 authored by Changhua Ji, Mausumee Guha, Xu Zhu, Jessica Whritenour, Michelle Hemkens, Susanna Tse, Gregory S. Walker, Ellen Evans, Nasir K. Khan, Martin B. Finkelstein, Ernesto Callegari, R. Scott ObachEnzalutamide and apalutamide are
two androgen receptor inhibitors
approved for the treatment of castration-resistant prostate cancer
(CRPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC),
respectively. Apalutamide is associated with an increased incidence
of skin rash above the placebo groups in the SPARTAN trial in nmCRPC
and in the TITAN trial in metastatic castration-sensitive prostate
cancer patients. On the contrary, the rate of skin rash across all
clinical trials (including PROSPER [nmCRPC]) for enzalutamide is similar
to the placebo. We hypothesized that the apalutamide-associated increased
skin rash in patients could be linked to a structural difference.
The 2-cyanophenyl and dimethyl moieties in enzalutamide are substituted
in apalutamide with 2-cyanopyridine and cyclobutyl, respectively.
In our evaluations, the 2-cyanopyridine moiety of apalutamide was
chemically reactive with the thiol nucleophile glutathione, resulting
in rearranged thiazoline products. Radiolabeled apalutamide, but not
radiolabeled enzalutamide, was shown to react with mouse and human
plasma proteins. Thiol nucleophiles decreased the extent of covalent
binding to the model protein bovine serum albumin, whereas amine and
alcohol nucleophiles had no effect, suggesting reactivity with cysteine
of proteins. Subcutaneous administration of apalutamide dose dependently
increased lymphocyte cellularity in draining lymph nodes in a mouse
drug allergy model (MDAM). Enzalutamide, and its known analogue RD162
in which the cyanophenyl was retained but the dimethyl was replaced
by cyclobutyl, demonstrated substantially less covalent binding activity
and negative results in the MDAM assay. Collectively, these data support
the hypothesis that the 2-cyanopyridine moiety in apalutamide may
react with cysteine in proteins forming haptens, which may trigger
an immune response, as indicated by the activity of apalutamide in
the MDAM assay, which in turn may be leading to increased potential
for skin rash versus placebo in patients in the SPARTAN and TITAN
clinical trials.
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nmCRPCapalutamide dose dependentlyenzalutamidenonmetastatic castration-resistant prostate cancerskin rashthiol nucleophile glutathioneMDAM assayMouse Drug Allergy Model Enzalutamideplaceboandrogen receptor inhibitorscovalent binding activitymetastatic castration-sensitive prostate cancer patients2- cyanopyridine moietyCRPCproteinmouse drug allergy modelTITANVitro Chemical Reactivity Studiesanalogue RD 162SPARTANcastration-resistant prostate cancer
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