ReviewProperties of FDA-approved small molecule protein kinase inhibitors: A 2022 update☆
Graphical Abstract
Section snippets
The importance of therapeutic protein kinase inhibitors
Because of genetic alterations such as translocations and mutations as well as overexpression, the dysregulation of protein kinase activity is implicated in the pathogenesis of autoimmune, cardiovascular, inflammatory, and nervous diseases as well as number of neoplasms. As a consequence, protein kinases have become one of the most important drug targets in the 21st century [1], [2]. Between 25% and 33% of the drug discovery efforts worldwide target these enzymes. The FDA approval of imatinib
Primary, secondary, and tertiary structures
The newly approved drugs described in this review interact with several protein kinases including the protein-serine/threonine kinases ROCK2 and CDK4/6 and the receptor protein-tyrosine kinases FGFR1/2/3/4, ErbB1/2/3/4, MET, and VEGFR1/2/3 so that the following description is generic. As initially described for PKA (protein kinase A) by Knighton et al., protein kinases possess a small N-terminal lobe and large C-terminal lobe (Fig. 1) [16]. The amino-terminal lobe is made up of a five-stranded
Protein kinase-inhibitor classification and inhibitor-binding pockets
Based upon previous studies [57], [60], [61], [62], we divided the small molecule protein kinase antagonists into seven main classes including reversible (Groups I, I½, II, III, IV, and V) and targeted covalent irreversible inhibitors (VI) as described in Table 5. We split the type I½ and type II inhibitors into A and B subtypes [31]. Subtype A drugs are those that extend past the gatekeeper residue into the back cleft. In comparison, subtype B drugs are those that do not extend into the back
Drug-enzyme interactions: infigratinib, tepotinib, tivozanib
Infigratinib is an anilino-pyrimidine derivative (Fig. 4A) [70] that is FDA-approved for the treatment of cholangiocarcinomas bearing FGFR2 fusion proteins [71]. We lack the X-ray crystal structure of infigratinib bound to FGFR2, but we have the structure of the drug bound to the related FGFR1 [70]. It shows that the pyrimidine nitrogen binds to the N–H group and the anilino N–H group binds to the backbone carbonyl group of the third hinge residue (A564) (Fig. 5A). The piperazine N–H binds to
Newly approved protein kinase antagonists without drug-enzyme structures: belumosudil, mobocertinib, trilaciclib
Belumosudil is an indazole-quinazoline derivative (Fig. 4D) that is FDA-approved for the third-line treatment of chronic graft vs. host disease [76], [77], [78]. This drug inhibits the ROCK2 protein-serine/threonine kinases that are downstream targets of the small RhoA, RhoB, and RhoC GTPases that are involved in diverse cellular activities including cell adhesion and motility, stress fiber and focal adhesion formation, actin cytoskeletal reorganization, remodeling of the extracellular matrix,
Lipinski’s rule of five (Ro5)
Pharmacologists and medicinal chemists have sought the physicochemical properties that result in drugs that are orally bioavailable. Lipinski’s rule of five (Ro5) is a computational and experimental methodology that is used to characterize membrane permeability, solubility, and efficacy in the drug-development setting [84]. It is a rule of thumb that evaluates drug-likeness and establishes whether an agent with specific pharmacological activities has properties suggesting that it would be
Epilogue and perspective
Although substantial progress has been made in the development and discovery of small molecule protein kinase antagonists since the FDA-approval of imatinib in 2001, this field remains in its early stages. The increased expression of many protein kinases in primary human tumors are understudied enzymes that may have important functions during tumorigenesis [98]. Moreover, these understudied enzymes may have therapeutic utility. Examples include cyclin-dependent protein kinase 12 (CDK12),
Conflict of interest
The author is unaware of any affiliations, memberships, or financial holdings that might be perceived as affecting the objectivity of this review.
Acknowledgments
I thank Dr. Albert J. Kooistra for providing the template depicted in Fig. 3 and Laura M. Roskoski for providing editorial and bibliographic assistance. I also thank Jasper Martinsek and Josie Rudnicki for their help in preparing the figures and W.S. Sheppard and Pasha Brezina for their help in structural analyses. The colored figures in this paper were evaluated to ensure that their perception was accurately conveyed to colorblind readers [107].
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This paper is dedicated to the memory of Dr. Phillip G. Schmid (1935-2021) – an early collaborator and friend.