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Structural Insight Into Protein Kinase D Small Molecule Inhibition

Carder, Evan (2014) Structural Insight Into Protein Kinase D Small Molecule Inhibition. Master's Thesis, University of Pittsburgh. (Unpublished)

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Protein kinase D (PKD) is a family of serine/threonine kinases that has emerged as a novel therapeutic target in multiple diseases; therefore, the development of small molecule inhibitors that abrogate PKD’s function has been an area of intense investigation. However, these efforts have not yet resulted in a PKD therapeutic that is available for clinical applications. Access to structural information can greatly accelerate this drug discovery process and allow future initiatives to benefit from structure-based drug design. Therefore, we employed both computational and experimental methods to investigate the important characteristics of PKD small molecule inhibitors that allow for excellent potency and selectivity. We found that type I ATP-competitive PKD inhibitors bind to the hinge region and position a hydrogen bond acceptor near the charged side chain of Lys612. An additional moiety (typically a basic amino group) capable of developing a critical salt bridge with Glu710 was shown to be important for improved affinity. Further analysis from inhibitor selectivity profiles suggested strategic functionalization in pocket II could potentially reduce kinase off-target effects. From our experimental investigation of CRT0066101 inhibition, we developed a chemical genetic tool kit for evaluating PKD function. Mutating the gatekeeper residue, Met659, to phenylalanine or tyrosine dramatically sensitized PKD to CRT0066101 inhibition. Conversely, mutating hinge residue, G664, to valine or isoleucine conferred resistance. Taken together, our study provides key insights into the chemical features associated with PKD inhibition, which will aid in the future development of a novel PKD therapeutic.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Carder, Evanejc26@pitt.eduEJC26
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorWang, Qiming Janeqjw1@pitt.eduQJW1
Committee ChairRomero, Guillermoggr@pitt.eduGGR
Committee MemberJiang, Yuyuj5@pitt.eduYUJ5
Committee MemberHu, Jingjih25@pitt.eduJIH25
Date: 12 December 2014
Date Type: Publication
Defense Date: 15 August 2014
Approval Date: 12 December 2014
Submission Date: 11 December 2014
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 59
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Pharmacology and Chemical Biology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Protein Kinase D, Small Molecule Inhibition, Drug Discovery
Date Deposited: 12 Dec 2014 20:11
Last Modified: 12 Dec 2019 06:15


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