Advances in covalent kinase inhibitors

Abdeldayem, Ayah; Raouf, Yasir S.; Constantinescu, Stefan N.; Moriggl, Richard; Gunning, Patrick T.

doi:10.1039/c9cs00720b

Cited by 184 publications

(234 citation statements)

References 417 publications

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“…Current JAK kinase inhibitors are ATP competitive analogues, with limited subtype selectivity. Some selectivity was achieved by covalently targeting a Cys residue in close proximity to the orthosteric pocket of JAK3 [17]. JAK kinase inhibitors have recently been employed for autoimmune-driven diseases including rheumatoid arthritis and exploration for basket trials in cancer, such as those performed for BRAF or HER2 kinase inhibitors, and could further propel clinical use [18].…”

Section: Introductionmentioning

confidence: 99%

Targeting STAT3 and STAT5 in Cancer

Araujo

Keserü

Gunning

et al. 2020

Cancers

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Section: Introductionmentioning

confidence: 99%

Targeting STAT3 and STAT5 in Cancer

Araujo

Keserü

Gunning

et al. 2020

Cancers

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“…The rapid-equilibrium inhibition constant for this inhibitor is K i = k −1 /k 1 = 0.0001/1.0 = 0.0001 µM = 0.1 nM. Now let us assume for the sake of discussion that the initial binding affinity of this molecule does not deteriorate by appending to it a chemically reactive covalent warhead such that the inactivation rate constant is k 2 = 0.1 s −1 , similar to a number known cases [4]. If so, the experimentally observable inhibition constant now increases thousand-fold, because K I = (k −1 + k 2 )/k 1 = (0.0001 + 0.1)/1 = 0.1001 µM = 100.1 nM.…”

Section: Steady-state K I Vs Rapid-equilibrium K Imentioning

confidence: 94%

“…Many medicines currently in use to treat various human diseases and symptoms are enzyme inhibitors. Furthermore, many important drugs and drug candidates are irreversible covalent inhibitors [1][2][3][4], which express their pharmacological effect by forming a permanent chemical bond with the protein target. Probably the most well known representative of this class is acetylsalicylate, or Aspirin, an irreversible covalent inhibitor of cyclooxygenase.…”

Section: Introductionmentioning

confidence: 99%

A two-point IC₅₀ method for evaluating the biochemical potency of irreversible enzyme inhibitors

Kuzmič¹

2020

Preprint

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Irreversible (covalent) enzyme inhibitors cannot be unambiguously ranked for biochemical potency by using IC50 values determined at a single point in time, because the same IC50 value could originate either from relatively low initial binding affinity accompanied by high chemical reactivity, or the other way around. To disambiguate the potency ranking of covalent inhibitors, here we describe a data-analytic procedure relying on two separate IC50 values, determined at two different reaction times. In the case of covalent inhibitors following the two-step kinetic mechanism E + I ⇔ E·I → EI, the two IC50 values alone can be used to estimate both the inhibition constant (Ki) as a measure of binding affinity and the inactivation rate constant (kinact) as a measure of chemical reactivity. In the case of covalent inhibitors following the one-step kinetic mechanism E + I → EI, a simple algebraic formula can be used to estimate the covalent efficiency constant (kinact/Ki) from a single experimental value of IC50. The two simplifying assumptions underlying the method are (1) zero inhibitor depletion, which implies that the inhibitor concentrations are always significantly higher than the enzyme concentration; and (2) constant reaction rate in the uninhibited control assay. The newly proposed method is validated by using a simulation study involving 64 irreversible inhibitors with covalent efficiency constants spanning seven orders of magnitude.

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“…This assumption is based on the classic rapid-equilibrium approximation in enzyme kinetics [2], where it is assumed that the formation of the covalent conjugate is very much slower than the dissociation of the noncovalent complex into its constituent components. However, an examination of existing experimental results reveals that the typical values of rate constants for the covalent inactivation step [3,Fig. 63] are not significantly smaller than the typical dissociation rate constants of therapeutically relevant enzyme inhibitors [4].…”

Section: Introductionmentioning

confidence: 99%

A Steady-State Algebraic Model for the Time Course of Covalent Enzyme Inhibition

Kuzmič¹

2020

Preprint

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This report describes an algebraic equation for the time course of irreversible enzyme inhibition following a two-step mechanism. In the first step, the enzyme and the inhibitor associate reversibly to form a non-covalent complex. In the second step, the noncovalent complex is irreversibly converted to the final covalent conjugate. Importantly, the algebraic derivation was performed under the steady-state approximation. Under the previously invoked rapid-equilibrium approximation [Kitz & Wilson (1962) J. Biol. Chem. 237, 3245] it is by definition assumed that the rate constant for the reversible dissociation of the initial noncovalent complex is very much faster than the rate constant for the irreversible inactivation step. In contrast, the steady-state algebraic equation reported here removes any restrictions on the relative magnitude of microscopic rate constants. The resulting formula was used in heuristic simulations designed to test the performance of the standard rapid-equilibrium kinetic model. The results show that if the inactivation rate constant is significantly higher than the dissociation rate constant, the conventional “kobs” method for evaluating the potency of covalent inhibitors in drug discovery is incapable of correctly distinguishing between the two-step inhibition mechanism and a simpler one-step variant, even for inhibitors that have very high binding affinity in the reversible noncovalent step.

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Advances in covalent kinase inhibitors

Abstract: This comprehensive review details recent advances, challenges and innovations in covalent kinase inhibition within a 10 year period (2007–2018).

Cited by 184 publications

References 417 publications

Targeting STAT3 and STAT5 in Cancer

Targeting STAT3 and STAT5 in Cancer

A two-point IC₅₀ method for evaluating the biochemical potency of irreversible enzyme inhibitors

A Steady-State Algebraic Model for the Time Course of Covalent Enzyme Inhibition

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Advances in covalent kinase inhibitors

Abstract: This comprehensive review details recent advances, challenges and innovations in covalent kinase inhibition within a 10 year period (2007–2018).

Cited by 184 publications

References 417 publications

Targeting STAT3 and STAT5 in Cancer

Targeting STAT3 and STAT5 in Cancer

A two-point IC50 method for evaluating the biochemical potency of irreversible enzyme inhibitors

A Steady-State Algebraic Model for the Time Course of Covalent Enzyme Inhibition

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A two-point IC₅₀ method for evaluating the biochemical potency of irreversible enzyme inhibitors