Probing Mechanisms of CYP3A Time-Dependent Inhibition Using a Truncated Model System.
Time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes may incur serious undesirable drug-drug interactions and in rare cases drug-induced idiosyncratic toxicity. The reactive metabolites are often generated through multiple sequential biotransformations and form adducts with CYP enzymes to inactivate their function. The complexity of these processes makes addressing TDI liability very challenging. Strategies to mitigate TDI are therefore highly valuable in discovering safe therapies to benefit patients. In this Letter, we disclose our simplified approach toward addressing CYP3A TDI liabilities, guided by metabolic mechanism hypotheses. By adding a methyl group onto the α carbon of a basic amine, TDI activities of both the truncated and full molecules (7a and 11) were completely eliminated. We propose that truncated molecules, albeit with caveats, may be used as surrogates for full molecules to investigate TDI.
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Xiaojing
X
Wang
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Minghua
M
Sun
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Connie
C
New
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Spencer
S
Nam
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Wesley P
WP
Blackaby
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Alastair J
AJ
Hodges
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
David
D
Nash
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Mizio
M
Matteucci
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Joseph P
JP
Lyssikatos
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Peter W
PW
Fan
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Suzanne
S
Tay
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Jae H
JH
Chang
CYP3A; Pim kinases; TDI; metabolic mechanism