Quantitatively Correlating interactions between three intrinsic kinetic
processes to in vivo protein kinase occupancy
Abstract
Background and Purpose: Excellent drug therapy is usually characterized
by longer duration with sufficiently high occupancy on desired target.
Except for classical pharmacokinetics (PK) contribution, binding
kinetics (BK) and target kinetics (TK) are emerging as key role. This
study aims to establish mathematical simulation model of kinase target
engagement by integrating three intrinsic kinetic processes (i.e., PK,
BK and kinase target kinetics, KTK) of interaction between kinase
inhibitors (KIs) and kinase protein. Experimental Approach: Five
half-life ratios, innovative pharmacokinetics-inhibition-kinase kinetics
(PIKK) and diagnostic line plots (DLPs) were generated to assess which
parameters were playing crucial role in the kinases target occupancy
(KTO) decline. PK-BK-TKT model was first developed by a series of
differential equations, and using this model simulated time courses of
protein kinase occupancy. And the temporal kinase selectivity (TKS)
method was firstly developed to judge inhibitor selectivity. Key
Results: By three visualization approaches, key rate-limiting factors
were first identified in kinase occupancy. We first simulated time
course profiles of interaction between 55 approved inhibitors with 55
clinically validated protein kinases. Subsequently, the TKS between 30
inhibitors and 55 protein kinases were generated, and 6 inhibitors were
identified as a highly selective chemical probe for their respective
primary target. Conclusion and Implications: The mathematic model can
describe the entire process of inhibitor-kinase interaction in-depth and
shows extensive applications in many aspects.