Protein Kinases in Drug Discovery: Rationale, Success, and Challenge

Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of “cryptic inhibitor-binding sites.” These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites. Transitional folding intermediates would become alternative targets in drug discovery, enabling the efficient development of potent kinase inhibitors.

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Protein Kinases in Drug Discovery

Handbook of Assay Development in Drug Discovery - Drug Discovery Series ◽

10.1201/9781420015706.ch1 ◽

2006 ◽

pp. 1-6

Author(s):

Jan Sechler ◽

Dana Johnson

Keyword(s):

Drug Discovery ◽

Protein Kinases

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Conformational transition paths harbor structures useful for aiding drug discovery and understanding enzymatic mechanisms in protein kinases

Protein Science ◽

10.1002/pro.2716 ◽

2015 ◽

Vol 25 (1) ◽

pp. 192-203 ◽

Cited By ~ 4

Author(s):

Chung F. Wong

Keyword(s):

Drug Discovery ◽

Protein Kinases ◽

Conformational Transition ◽

Transition Paths ◽

Enzymatic Mechanisms

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Pocketome of Human Kinases: Prioritizing the ATP Binding Sites of (Yet) Untapped Protein Kinases for Drug Discovery

Journal of Chemical Information and Modeling ◽

10.1021/ci500624s ◽

2015 ◽

Vol 55 (3) ◽

pp. 538-549 ◽

Cited By ~ 28

Author(s):

Andrea Volkamer ◽

Sameh Eid ◽

Samo Turk ◽

Sabrina Jaeger ◽

Friedrich Rippmann ◽

...

Keyword(s):

Drug Discovery ◽

Protein Kinases ◽

Binding Sites ◽

Atp Binding

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Parasite Mitogen-Activated Protein Kinases as Drug Discovery Targets to Treat Human Protozoan Pathogens

Journal of Signal Transduction ◽

10.1155/2011/971968 ◽

2011 ◽

Vol 2011 ◽

pp. 1-16 ◽

Cited By ~ 19

Author(s):

Michael J. Brumlik ◽

Srilakshmi Pandeswara ◽

Sara M. Ludwig ◽

Kruthi Murthy ◽

Tyler J. Curiel

Keyword(s):

Drug Discovery ◽

Protein Kinases ◽

Diverse Group ◽

Human Pathogens ◽

Mitogen Activated Protein Kinases ◽

Obligate Intracellular ◽

Intracellular Parasites ◽

Mitogen Activated Protein ◽

Unicellular Organisms ◽

Novel Drug

Protozoan pathogens are a highly diverse group of unicellular organisms, several of which are significant human pathogens. One group of protozoan pathogens includes obligate intracellular parasites such as agents of malaria, leishmaniasis, babesiosis, and toxoplasmosis. The other group includes extracellular pathogens such as agents of giardiasis and amebiasis. An unfortunate unifying theme for most human protozoan pathogens is that highly effective treatments for them are generally lacking. We will review targeting protozoan mitogen-activated protein kinases (MAPKs) as a novel drug discovery approach towards developing better therapies, focusing on Plasmodia, Leishmania, and Toxoplasma, about which the most is known.

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