RT Journal Article
SR Electronic
T1 Slow tight binding inhibition of CYP17A1 by abiraterone redefines its kinetic selectivity and dosing regimen
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.120.265868
DO 10.1124/jpet.120.265868
A1 Eleanor Jing Yi Cheong
A1 Pramod C Nair
A1 Rebecca Wan Yi Neo
A1 Ho Thanh Tu
A1 Fu Lin
A1 Edmund Chiong
A1 Kesavan Esuvaranathan
A1 Hao Fan
A1 Russell Szmulewitz
A1 Cody J Peer
A1 William D Figg
A1 Christina Li Lin Chai
A1 John O. Miners
A1 Eric Chun Yong Chan
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/06/17/jpet.120.265868.abstract
AB Substantial evidence underscores the clinical efficacy of inhibiting cytochrome P450 17A1 (CYP17A1)-mediated androgen biosynthesis by abiraterone for treatment of prostate oncology. Previous structural analysis and in vitro assays revealed inconsistencies surrounding the nature and potency of CYP17A1 inhibition by abiraterone. Here, we establish that abiraterone is a slow, tight binding inhibitor of CYP17A1, with initial weak binding preceding the subsequent slow isomerization to a high affinity CYP17A1-abiraterone complex (EI*). The in vitro binding affinity of abiraterone to CYP17A1 (-12.8 kcal/mol for Ki* = 0.39 nM) was quantitatively consistent with its in silico predicted binding free energy (-14.5 kcal/mol). Prolonged suppression of dehydroepiandrosterone (DHEA) concentrations observed in VCaP cells following abiraterone washout corroborated its protracted CYP17A1 engagement. Molecular dynamics simulations illuminated potential structural determinants underlying the rapid reversible binding characterizing the two-step induced fit model. Given the extended residence time (42 h) of abiraterone within the CYP17A1 active site, in silico simulations demonstrated sustained target engagement even when most abiraterone has been eliminated systemically. Subsequent pharmacokinetic-pharmacodynamic (PK-PD) modelling linking time-dependent CYP17A1 occupancy to in vitro steroidogenic dynamics predicted comparable suppression of downstream DHEA-sulphate at both 1000 and 500 mg doses of abiraterone acetate. This enabled mechanistic rationalization of a clinically reported PK-PD disconnect, where equipotent reduction of downstream plasma DHEA-sulphate levels was achieved despite a lower systemic exposure of abiraterone. Our novel findings provide the impetus for re-evaluating the current dosing paradigm of abiraterone, with the aim of preserving PD efficacy while mitigating its dose-dependent adverse effects and financial burden.SIGNIFICANCE STATEMENT With the advent of novel molecularly targeted anticancer modalities, it is becoming increasingly evident that optimal dose selection must necessarily be predicated on mechanistic characterization of the relationships between target exposure, drug-target interactions and pharmacodynamic endpoints. Nevertheless, efficacy has always been perceived as being exclusively synonymous with affinity-based measurements of drug-target binding. This work demonstrates how elucidating the slow, tight binding inhibition of CYP17A1 by abiraterone via in vitro and in silico analyses was pivotal in establishing the role of kinetic selectivity in mediating time-dependent CYP17A1 engagement and eventually downstream efficacy outcomes.