Review
Properties of FDA-approved small molecule protein kinase inhibitors: A 2022 update

https://doi.org/10.1016/j.phrs.2021.106037Get rights and content

Abstract

Owing to the dysregulation of protein kinase activity in many diseases including cancer, this enzyme family has become one of the most important drug targets in the 21st century. There are 68 FDA-approved therapeutic agents that target about two dozen different protein kinases and six of these drugs were approved in 2021. Of the approved drugs, twelve target protein-serine/threonine protein kinases, four are directed against dual specificity protein kinases (MEK1/2), thirteen block nonreceptor protein-tyrosine kinases, and 39 target receptor protein-tyrosine kinases. The data indicate that 58 of these drugs are prescribed for the treatment of neoplasms (49 against solid tumors including breast, lung, and colon, five against nonsolid tumors such as leukemias, and four against both solid and nonsolid tumors: acalabrutinib, ibrutinib, imatinib, and midostaurin). Three drugs (baricitinib, tofacitinib, upadacitinib) are used for the treatment of inflammatory diseases including rheumatoid arthritis. Of the 68 approved drugs, eighteen are used in the treatment of multiple diseases. The following six drugs received FDA approval in 2021 for the treatment of these specified diseases: belumosudil (graft vs. host disease), infigratinib (cholangiocarcinomas), mobocertinib and tepotinib (specific forms of non-small cell lung cancer), tivozanib (renal cell carcinoma), and trilaciclib (to decrease chemotherapy-induced myelosuppression). All of the FDA-approved drugs are orally effective with the exception of netarsudil, temsirolimus, and the newly approved trilaciclib. This review summarizes the physicochemical properties of all 68 FDA-approved small molecule protein kinase inhibitors including lipophilic efficiency and ligand efficiency.

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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