Feature Review
FDA-approved small-molecule kinase inhibitors

https://doi.org/10.1016/j.tips.2015.04.005Get rights and content

Highlights

  • The classification of small-molecule kinase inhibitors is delineated.

  • All FDA-approved small-molecule kinase inhibitors (at April 2015) are presented according to binding mechanism and common structural features.

  • The current landscape and major challenges in kinase inhibition are discussed.

  • Possible future directions in developing novel kinase inhibitors are proposed.

Kinases have emerged as one of the most intensively pursued targets in current pharmacological research, especially for cancer, due to their critical roles in cellular signaling. To date, the US FDA has approved 28 small-molecule kinase inhibitors, half of which were approved in the past 3 years. While the clinical data of these approved molecules are widely presented and structure–activity relationship (SAR) has been reported for individual molecules, an updated review that analyzes all approved molecules and summarizes current achievements and trends in the field has yet to be found. Here we present all approved small-molecule kinase inhibitors with an emphasis on binding mechanism and structural features, summarize current challenges, and discuss future directions in this field.

Section snippets

Kinase inhibitors: a burgeoning field

The past one and a half decades witnessed an unparalleled success in the development of therapeutically useful kinase inhibitors, powered by tremendous progress in both academic and industrial settings. The milestone approval of the first kinase inhibitor, imatinib, in 2001 by the FDA, was followed by a slow yet steady approval of kinase inhibitors in the first 10 years of this century with almost one new approval per year on average. Concurrently, our understanding of kinase signaling networks

Kinases

Kinases catalyze the transfer of the γ-phosphate group of ATP onto a substrate, mediate most signal transductions [1], and regulate various cellular activities, including proliferation, survival, apoptosis, metabolism, transcription, differentiation, and a wide array of other cellular processes [2]. Accumulating pharmacological and pathological evidence has revealed that kinases are promising drug targets for the treatment of numerous diseases [3] such as cancers 4, 5, 6, inflammatory diseases 7

Kinase inhibitors

Although diverse in primary amino acid sequence, the human kinases share a great degree of similarity in their 3D structures, especially in their catalytically active kinase domain where the ATP-binding pocket is located: a β sheet containing N-terminal lobe (N-lobe), an α helix-dominated C-terminal lobe (C-lobe), and a connecting hinge region [21]. ATP binds in the cleft formed between the N- and C-lobes and most kinase inhibitors perturb binding through interactions with this region. A

Reversible non-receptor tyrosine kinase (NRTK) inhibitors

BCR-Abl was the first kinase for which a small-molecule inhibitor was successfully approved [32]. On another note, being the first approved kinase inhibitor and a revolutionary success for the treatment of chronic myeloid leukemia (CML) [17], imatinib has been the subject of various SAR studies to guide the design of next-generation inhibitors and provide a deeper understanding of the inhibition mechanism. Considerable efforts seek to develop inhibitors based on structural features derived from

Approved irreversible protein kinase inhibitors

The EGFR inhibitor afatinib was the first clinically approved irreversible kinase inhibitor, followed shortly by ibrutinib in November 2013. The approval of these two molecules validates the strategy of incorporating Michael acceptor functionality in small-molecule inhibitors to form a covalent bond with a cysteine residue in the active site of kinases. This type of irreversible inhibitor is expected to achieve greater specificity and potency, although concerns have been raised regarding

Approved serine/threonine kinase inhibitors

The serine/threonine kinase B-Raf, one of the three isoforms of the Raf family, has been established as an attractive anticancer target [81]. Replacement of Val600 with Glu600 within the activation loop of the kinase domain accounts for 90% of B-Raf mutations [82], resulting in destabilization of the inactive conformation, elevated activation of the MAPK pathway, and enhanced promotion of cell survival and proliferation. Efforts in developing small-molecule kinase inhibitors led to the approved

Approved lipid kinase inhibitors

Lipid kinases, such as PI3Ks, were discovered as early as the 1980s [95]. It has been convincingly established that activation and mutation of PI3Ks and other key components of this signaling pathway play key roles in various stages of tumor development [96]. Considerable efforts from both academia and industry have been involved in the development of small-molecule lipid kinases since the 1980s, but the clinical success of these inhibitors was minimal until the approval of the first lipid

Limitations and challenges

Kinase-based drug discovery has achieved dramatic progress in the past 15 years. Although kinase inhibition represents a young therapeutic strategy compared with other, traditional tactics targeting, for example, G protein-coupled receptors (GPCRs), membrane channels and transporters, and protease, an analysis of FDA-approved cancer drugs since the 1980s reveals that kinases have already overtaken GPCRs as the most sought-after cellular targets for cancer treatment [108]. Our analysis of all

Future directions

Based on the current trends discussed above, some challenging questions that might serve as directions for future development of small-molecule kinase inhibitors and push the boundary of the research in this field need to be addressed appropriately.

First, the fact that current kinase inhibitors focus on only a small subset of the human kinome indicates that many kinases are neglected. Thus, there is a need to develop tools and selective probes to uncover the functions of these unknown kinases

Concluding remarks

Groundbreaking understanding of cellular signaling cascades at the molecular level has led to major advances in kinase research over the past decades. The dramatic progress in applying the strategy of targeted kinase inhibition in the past 15 years has been highlighted by the successful approval of no less than 28 small-molecule kinase inhibitors. An analysis based on co-crystal structures of all approved inhibitors with a focus on binding mechanism and structural features is presented here to

Acknowledgements

The Lundbeck Foundation (R140-2013-13835) is gratefully acknowledged for financial support. The authors thank Professor David A. Tanner for proofreading the manuscript.

References (110)

  • A.J. Lamontanara

    Mechanisms of resistance to BCR-ABL and other kinase inhibitors

    Biochim. Biophys. Acta

    (2013)
  • H.L. Geyer et al.

    Therapy for myeloproliferative neoplasms: when, which agent, and how?

    Blood

    (2014)
  • J.E. Chrencik

    Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6

    J. Mol. Biol.

    (2010)
  • N.K. Williams

    Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains

    J. Mol. Biol.

    (2009)
  • C-H. Yun

    Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity

    Cancer Cell

    (2007)
  • K.S. Gajiwala

    Insights into the aberrant activity of mutant EGFR kinase domain and drug recognition

    Structure

    (2013)
  • J. Stamos

    Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor (erlotinib with EGFR)

    J. Biol. Chem.

    (2002)
  • C. Qiu

    Mechanism of activation and inhibition of the HER4/ErbB4 kinase

    Structure

    (2008)
  • P.P. Knowles

    Structure and chemical inhibition of the RET tyrosine kinase domain

    J. Biol. Chem.

    (2006)
  • C. Basilico

    A high affinity hepatocyte growth factor-binding site in the immunoglobulin-like region of Met

    J. Biol. Chem.

    (2008)
  • P.T.C. Wan

    Mechanism of activation of the RAF–ERK signaling pathway by oncogenic mutations of B-RAF

    Cell

    (2004)
  • Q. Dong

    Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer

    Bioorg. Med. Chem. Lett.

    (2011)
  • F. Chiarini

    Current treatment strategies for inhibiting mTOR in cancer

    Trends Pharmacol. Sci.

    (2015)
  • B.D. Cheson

    CLL and NHL: the end of chemotherapy?

    Blood

    (2014)
  • L.N. Johnson et al.

    Structural basis for control by phosphorylation

    Chem. Rev.

    (2001)
  • J.A. Adams

    Kinetic and catalytic mechanisms of protein kinases

    Chem. Rev.

    (2001)
  • W.W. Ma et al.

    Novel agents on the horizon for cancer therapy

    CA Cancer J. Clin.

    (2009)
  • J.D. Clark

    Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases

    J. Med. Chem.

    (2014)
  • P.J. Barnes

    New anti-inflammatory targets for chronic obstructive pulmonary disease

    Nat. Rev. Drug Discov.

    (2013)
  • F. Muth

    Tetra-substituted pyridinylimidazoles as dual inhibitors of p38α mitogen-activated protein kinase and c-Jun N-terminal kinase 3 for potential treatment of neurodegenerative diseases

    J. Med. Chem.

    (2015)
  • R. Kikuchi

    An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease

    Nat. Med.

    (2014)
  • A.S. Banks

    An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ

    Nature

    (2015)
  • P. Cohen

    The origins of protein phosphorylation

    Nat. Cell Biol.

    (2002)
  • L.S. Steelman

    JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis

    Leukemia

    (2004)
  • The UniProt Consortium

    Update on activities at the Universal Protein Resource (UniProt) in 2013

    Nucleic Acids Res.

    (2013)
  • G. Manning

    The protein kinase complement of the human genome

    Science

    (2002)
  • E. Pennisi

    ENCODE project writes eulogy for junk DNA

    Science

    (2012)
  • D. Knighton

    Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase

    Science

    (1991)
  • M. Tong et al.

    Targeting conformational plasticity of protein kinases

    ACS Chem. Biol.

    (2015)
  • M.E.M. Noble

    Protein kinase inhibitors: insights into drug design from structure

    Science

    (2004)
  • K.J. Cox

    Tinkering outside the kinase ATP box: allosteric (type IV) and bivalent (type V) inhibitors of protein kinases

    Future Med. Chem.

    (2010)
  • V. Lamba et al.

    New directions in targeting protein kinases: focusing upon true allosteric and bivalent inhibitors

    Curr. Pharm. Des.

    (2012)
  • P. Yaish

    Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors

    Science

    (1988)
  • A. Gazit

    Tyrphostins I: synthesis and biological activity of protein tyrosine kinase inhibitors

    J. Med. Chem.

    (1989)
  • L.K. Gavrin et al.

    Approaches to discover non-ATP site kinase inhibitors

    MedChemComm

    (2013)
  • A. Levitzki

    Tyrosine kinase inhibitors: views of selectivity, sensitivity, and clinical performance

    Annu. Rev. Pharmacol. Toxicol.

    (2013)
  • B.J. Druker

    Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia

    N. Eng. J. Med.

    (2001)
  • G.E. Winter

    Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML

    Nat. Chem. Biol.

    (2012)
  • B. Nagar

    Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571)

    Cancer Res.

    (2002)
  • L. Ma

    A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia

    Sci. Transl. Med.

    (2014)
  • Cited by (781)

    View all citing articles on Scopus
    View full text