Literature DB >> 26985301

Discovery of a Novel 2,6-Disubstituted Glucosamine Series of Potent and Selective Hexokinase 2 Inhibitors.

Hong Lin1, Jin Zeng1, Ren Xie1, Mark J Schulz1, Rosanna Tedesco1, Junya Qu1, Karl F Erhard1, James F Mack1, Kaushik Raha1, Alan R Rendina1, Lawrence M Szewczuk1, Patricia M Kratz1, Anthony J Jurewicz1, Ted Cecconie1, Stan Martens1, Patrick J McDevitt1, John D Martin1, Stephenie B Chen1, Yong Jiang1, Leng Nickels1, Benjamin J Schwartz1, Angela Smallwood1, Baoguang Zhao1, Nino Campobasso1, Yanqiu Qian1, Jacques Briand1, Cynthia M Rominger1, Catherine Oleykowski1, Mary Ann Hardwicke1, Juan I Luengo1.   

Abstract

A novel series of potent and selective hexokinase 2 (HK2) inhibitors, 2,6-disubstituted glucosamines, has been identified based on HTS hits, exemplified by compound 1. Inhibitor-bound crystal structures revealed that the HK2 enzyme could adopt an "induced-fit" conformation. The SAR study led to the identification of potent HK2 inhibitors, such as compound 34 with greater than 100-fold selectivity over HK1. Compound 25 inhibits in situ glycolysis in a UM-UC-3 bladder tumor cell line via (13)CNMR measurement of [3-(13)C]lactate produced from [1,6-(13)C2]glucose added to the cell culture.

Entities:  

Keywords:  Hexokinase 2 inhibitor; crystal structure; structure−activity relationship selectivity

Year:  2015        PMID： 26985301      PMCID： PMC4789681          DOI： 10.1021/acsmedchemlett.5b00214

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  10 in total

Review 1.  Hexokinase-2 bound to mitochondria: cancer's stygian link to the "Warburg Effect" and a pivotal target for effective therapy.

Authors:  Saroj P Mathupala; Young H Ko; Peter L Pedersen
Journal:  Semin Cancer Biol       Date:  2008-12-03       Impact factor: 15.707

2.  The structure of mammalian hexokinase-1.

Authors:  A M Mulichak; J E Wilson; K Padmanabhan; R M Garavito
Journal:  Nat Struct Biol       Date:  1998-07

Review 3.  Glycolysis inhibition for anticancer treatment.

Authors:  H Pelicano; D S Martin; R-H Xu; P Huang
Journal:  Oncogene       Date:  2006-08-07       Impact factor: 9.867

4.  Crystal structure of the human glucose transporter GLUT1.

Authors:  Dong Deng; Chao Xu; Pengcheng Sun; Jianping Wu; Chuangye Yan; Mingxu Hu; Nieng Yan
Journal:  Nature       Date:  2014-05-18       Impact factor: 49.962

Review 5.  Aberrant glycolytic metabolism of cancer cells: a remarkable coordination of genetic, transcriptional, post-translational, and mutational events that lead to a critical role for type II hexokinase.

Authors:  S P Mathupala; A Rempel; P L Pedersen
Journal:  J Bioenerg Biomembr       Date:  1997-08       Impact factor: 2.945

6.  Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention.

Authors:  Peter L Pedersen; Saroj Mathupala; Annette Rempel; J F Geschwind; Young Hee Ko
Journal:  Biochim Biophys Acta       Date:  2002-09-10

7.  Evaluation of the role of hexokinase type II in cellular proliferation and apoptosis using human hepatocellular carcinoma cell lines.

Authors:  Keun Jae Ahn; Hee Sung Hwang; Jeon Han Park; Seong Hye Bang; Won Jun Kang; Mijin Yun; Jong Doo Lee
Journal:  J Nucl Med       Date:  2009-08-18       Impact factor: 10.057

8.  Stable RNA interference of hexokinase II gene inhibits human colon cancer LoVo cell growth in vitro and in vivo.

Authors:  Qiuping Peng; Qi Zhou; Jinming Zhou; Daping Zhong; Feng Pan; Houjie Liang
Journal:  Cancer Biol Ther       Date:  2008-04-28       Impact factor: 4.742

9.  Human hexokinase II: sequence and homology to other hexokinases.

Authors:  S S Deeb; M Malkki; M Laakso
Journal:  Biochem Biophys Res Commun       Date:  1993-11-30       Impact factor: 3.575

10.  Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer.

Authors:  Qi Wang; Prashanth T Bhaskar; Krushna C Patra; Luke Miller; Zebin Wang; Will Wheaton; Navdeep Chandel; Markku Laakso; William J Muller; Eric L Allen; Abhishek K Jha; Gromoslaw A Smolen; Michelle F Clasquin; Brooks Robey; Nissim Hay
Journal:  Cancer Cell       Date:  2013-08-01       Impact factor: 31.743
  10 in total
  23 in total

1.  Glycolytic inhibition: an effective strategy for developing calorie restriction mimetics.

Authors:  Donald K Ingram; George S Roth
Journal:  Geroscience       Date:  2020-11-12       Impact factor: 7.713

Review 2.  Exploiting Metabolic Vulnerabilities of Cancer with Precision and Accuracy.

Authors:  Adam J Wolpaw; Chi V Dang
Journal:  Trends Cell Biol       Date:  2017-12-08       Impact factor: 20.808

3.  Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation.

Authors:  Katherine Tech; Andrey P Tikunov; Hamza Farooq; A Sorana Morrissy; Jessica Meidinger; Taylor Fish; Sarah C Green; Hedi Liu; Yisu Li; Andrew J Mungall; Richard A Moore; Yussanne Ma; Steven J M Jones; Marco A Marra; Matthew G Vander Heiden; Michael D Taylor; Jeffrey M Macdonald; Timothy R Gershon
Journal:  Cancer Res       Date:  2017-05-17       Impact factor: 12.701

Review 4.  Competitive glucose metabolism as a target to boost bladder cancer immunotherapy.

Authors:  Julieta Afonso; Lúcio L Santos; Adhemar Longatto-Filho; Fátima Baltazar
Journal:  Nat Rev Urol       Date:  2020-01-17       Impact factor: 14.432

5.  Hexokinase 2 is targetable for HK1 negative, HK2 positive tumors from a wide variety of tissues of origin.

Authors:  Shili Xu; Arthur Catapang; Hanna M Doh; Nicholas A Bayley; Jason T Lee; Daniel Braas; Thomas G Graeber; Harvey R Herschman
Journal:  J Nucl Med       Date:  2018-06-07       Impact factor: 10.057

6.  Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2.

Authors:  Wei Li; Mengzhu Zheng; Shuangping Wu; Suyu Gao; Mei Yang; Zhimei Li; Qiuxia Min; Weiguang Sun; Lixia Chen; Guangya Xiang; Hua Li
Journal:  J Exp Clin Cancer Res       Date:  2017-04-20

7.  The catalytic inactivation of the N-half of human hexokinase 2 and structural and biochemical characterization of its mitochondrial conformation.

Authors:  Mir Hussain Nawaz; Juliana C Ferreira; Lyudmila Nedyalkova; Haizhong Zhu; César Carrasco-López; Serdal Kirmizialtin; Wael M Rabeh
Journal:  Biosci Rep       Date:  2018-02-21       Impact factor: 3.840

8.  A precision therapeutic strategy for hexokinase 1-null, hexokinase 2-positive cancers.

Authors:  Shili Xu; Arthur Catapang; Daniel Braas; Linsey Stiles; Hanna M Doh; Jason T Lee; Thomas G Graeber; Robert Damoiseaux; Orian Shirihai; Harvey R Herschman
Journal:  Cancer Metab       Date:  2018-06-28

9.  Multi-Functional MPT Protein as a Therapeutic Agent against Mycobacterium tuberculosis.

Authors:  Jae-Sung Kim; Euni Cho; Seok-Jun Mun; Sojin Kim; Sun-Young Kim; Dong-Gyu Kim; Wooic Son; Hye-In Jeon; Hyo-Keun Kim; Young-Jin Jeong; Sein Jang; Hyun-Sung Kim; Chul-Su Yang
Journal:  Biomedicines       Date:  2021-05-13

10.  Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin.

Authors:  Dannielle DeWaal; Veronique Nogueira; Alexander R Terry; Krushna C Patra; Sang-Min Jeon; Grace Guzman; Jennifer Au; Christopher P Long; Maciek R Antoniewicz; Nissim Hay
Journal:  Nat Commun       Date:  2018-01-31       Impact factor: 14.919
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