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Title: Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)

Abstract

Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.

Authors:
ORCiD logo [1];  [2];  [2];  [2];  [3];  [3];  [4];  [4];  [4];  [4];  [4];  [2];  [2];  [3];  [4];  [3];  [3];  [2];  [2];  [1] more »;  [1];  [2];  [4];  [4];  [3];  [2];  [4];  [1];  [4];  [1];  [3];  [2];  [2] « less
  1. Medicine Design, Pfizer Inc., 1 Portland Street, Cambridge, Massachusetts 02139, United States
  2. Internal Medicine, Pfizer Inc., 1 Portland Street, Cambridge, Massachusetts 02139, United States
  3. Structural Biology and Biophysics, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States
  4. Medicine Design, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1405008
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Medicinal Chemistry; Journal Volume: 60; Journal Issue: 18
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES

Citation Formats

Huard, Kim, Ahn, Kay, Amor, Paul, Beebe, David A., Borzilleri, Kris A., Chrunyk, Boris A., Coffey, Steven B., Cong, Yang, Conn, Edward L., Culp, Jeffrey S., Dowling, Matthew S., Gorgoglione, Matthew F., Gutierrez, Jemy A., Knafels, John D., Lachapelle, Erik A., Pandit, Jayvardhan, Parris, Kevin D., Perez, Sylvie, Pfefferkorn, Jeffrey A., Price, David A., Raymer, Brian, Ross, Trenton T., Shavnya, Andre, Smith, Aaron C., Subashi, Timothy A., Tesz, Gregory J., Thuma, Benjamin A., Tu, Meihua, Weaver, John D., Weng, Yan, Withka, Jane M., Xing, Gang, and Magee, Thomas V. Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK). United States: N. p., 2017. Web. doi:10.1021/acs.jmedchem.7b00947.
Huard, Kim, Ahn, Kay, Amor, Paul, Beebe, David A., Borzilleri, Kris A., Chrunyk, Boris A., Coffey, Steven B., Cong, Yang, Conn, Edward L., Culp, Jeffrey S., Dowling, Matthew S., Gorgoglione, Matthew F., Gutierrez, Jemy A., Knafels, John D., Lachapelle, Erik A., Pandit, Jayvardhan, Parris, Kevin D., Perez, Sylvie, Pfefferkorn, Jeffrey A., Price, David A., Raymer, Brian, Ross, Trenton T., Shavnya, Andre, Smith, Aaron C., Subashi, Timothy A., Tesz, Gregory J., Thuma, Benjamin A., Tu, Meihua, Weaver, John D., Weng, Yan, Withka, Jane M., Xing, Gang, & Magee, Thomas V. Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK). United States. doi:10.1021/acs.jmedchem.7b00947.
Huard, Kim, Ahn, Kay, Amor, Paul, Beebe, David A., Borzilleri, Kris A., Chrunyk, Boris A., Coffey, Steven B., Cong, Yang, Conn, Edward L., Culp, Jeffrey S., Dowling, Matthew S., Gorgoglione, Matthew F., Gutierrez, Jemy A., Knafels, John D., Lachapelle, Erik A., Pandit, Jayvardhan, Parris, Kevin D., Perez, Sylvie, Pfefferkorn, Jeffrey A., Price, David A., Raymer, Brian, Ross, Trenton T., Shavnya, Andre, Smith, Aaron C., Subashi, Timothy A., Tesz, Gregory J., Thuma, Benjamin A., Tu, Meihua, Weaver, John D., Weng, Yan, Withka, Jane M., Xing, Gang, and Magee, Thomas V. Tue . "Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)". United States. doi:10.1021/acs.jmedchem.7b00947.
@article{osti_1405008,
title = {Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)},
author = {Huard, Kim and Ahn, Kay and Amor, Paul and Beebe, David A. and Borzilleri, Kris A. and Chrunyk, Boris A. and Coffey, Steven B. and Cong, Yang and Conn, Edward L. and Culp, Jeffrey S. and Dowling, Matthew S. and Gorgoglione, Matthew F. and Gutierrez, Jemy A. and Knafels, John D. and Lachapelle, Erik A. and Pandit, Jayvardhan and Parris, Kevin D. and Perez, Sylvie and Pfefferkorn, Jeffrey A. and Price, David A. and Raymer, Brian and Ross, Trenton T. and Shavnya, Andre and Smith, Aaron C. and Subashi, Timothy A. and Tesz, Gregory J. and Thuma, Benjamin A. and Tu, Meihua and Weaver, John D. and Weng, Yan and Withka, Jane M. and Xing, Gang and Magee, Thomas V.},
abstractNote = {Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.},
doi = {10.1021/acs.jmedchem.7b00947},
journal = {Journal of Medicinal Chemistry},
number = 18,
volume = 60,
place = {United States},
year = {Tue May 23 00:00:00 EDT 2017},
month = {Tue May 23 00:00:00 EDT 2017}
}