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Development of thioquinazolinones, allosteric Chk1 kinase inhibitors.

Converso A, Hartingh T, Garbaccio RM, Tasber E, Rickert K, Fraley ME, Yan Y, Kreatsoulas C, Stirdivant S, Drakas B, Walsh ES, Hamilton K, Buser CA, Mao X, Abrams MT, Beck SC, Tao W, Lobell R, Sepp-Lorenzino L, Zugay-Murphy J, Sardana V, Munshi SK, Jezequel-Sur SM, Zuck PD, Hartman GD
Bioorg Med Chem Lett 19 1240-4 (2009)
Cited: 35 times
EuropePMC logo PMID: 19155174

Abstract

A high throughput screening campaign was designed to identify allosteric inhibitors of Chk1 kinase by testing compounds at high concentration. Activity was then observed at K(m) for ATP and at near-physiological concentrations of ATP. This strategy led to the discovery of a non-ATP competitive thioquinazolinone series which was optimized for potency and stability. An X-ray crystal structure for the complex of our best inhibitor bound to Chk1 was solved, indicating that it binds to an allosteric site approximately 13A from the ATP binding site. Preliminary data is presented for several of these compounds.

Reviews - 3f9n mentioned but not cited (3)

  1. Ten things you should know about protein kinases: IUPHAR Review 14. Fabbro D, Cowan-Jacob SW, Moebitz H. Br J Pharmacol 172 2675-2700 (2015)
  2. Structure-based design, discovery and development of checkpoint kinase inhibitors as potential anticancer therapies. Matthews TP, Jones AM, Collins I. Expert Opin Drug Discov 8 621-640 (2013)
  3. Therapeutic Targeting the Allosteric Cysteinome of RAS and Kinase Families. Li L, Meyer C, Zhou ZW, Elmezayen A, Westover K. J Mol Biol 434 167626 (2022)

Articles - 3f9n mentioned but not cited (3)

  1. Measuring and interpreting the selectivity of protein kinase inhibitors. Smyth LA, Collins I. J Chem Biol 2 131-151 (2009)
  2. Discovery of novel checkpoint kinase 1 inhibitors by virtual screening based on multiple crystal structures. Li Y, Kim DJ, Ma W, Lubet RA, Bode AM, Dong Z. J Chem Inf Model 51 2904-2914 (2011)
  3. Computational Analysis of Crystallization Additives for the Identification of New Allosteric Sites. Fogha J, Diharce J, Obled A, Aci-Sèche S, Bonnet P. ACS Omega 5 2114-2122 (2020)


Reviews citing this publication (10)

  1. Kinase-targeted cancer therapies: progress, challenges and future directions. Bhullar KS, Lagarón NO, McGowan EM, Parmar I, Jha A, Hubbard BP, Rupasinghe HPV. Mol Cancer 17 48 (2018)
  2. Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics. Ma CX, Janetka JW, Piwnica-Worms H. Trends Mol Med 17 88-96 (2011)
  3. Fine-tuning multiprotein complexes using small molecules. Thompson AD, Dugan A, Gestwicki JE, Mapp AK. ACS Chem Biol 7 1311-1320 (2012)
  4. Harnessing allostery: a novel approach to drug discovery. Lu S, Li S, Zhang J. Med Res Rev 34 1242-1285 (2014)
  5. Drug discovery and the human kinome: recent trends. Eglen R, Reisine T. Pharmacol Ther 130 144-156 (2011)
  6. Quinazoline derivatives as potential anticancer agents: a patent review (2007 - 2010). Marzaro G, Guiotto A, Chilin A. Expert Opin Ther Pat 22 223-252 (2012)
  7. Kinase Atlas: Druggability Analysis of Potential Allosteric Sites in Kinases. Yueh C, Rettenmaier J, Xia B, Hall DR, Alekseenko A, Porter KA, Barkovich K, Keseru G, Whitty A, Wells JA, Vajda S, Kozakov D. J Med Chem 62 6512-6524 (2019)
  8. Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia. K Bhanumathy K, Balagopal A, Vizeacoumar FS, Vizeacoumar FJ, Freywald A, Giambra V. Cancers (Basel) 13 E184 (2021)
  9. Checkpoint kinase inhibitors: a patent review (2009 - 2010). Lainchbury M, Collins I. Expert Opin Ther Pat 21 1191-1210 (2011)
  10. The hunt for antimitotic agents: an overview of structure-based design strategies. Dube D, Tiwari P, Kaur P. Expert Opin Drug Discov 11 579-597 (2016)

Articles citing this publication (19)

  1. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Zhang J, Adrián FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, Sim T, Powers J, Dierks C, Sun F, Guo GR, Ding Q, Okram B, Choi Y, Wojciechowski A, Deng X, Liu G, Fendrich G, Strauss A, Vajpai N, Grzesiek S, Tuntland T, Liu Y, Bursulaya B, Azam M, Manley PW, Engen JR, Daley GQ, Warmuth M, Gray NS. Nature 463 501-506 (2010)
  2. Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition. Wu WI, Voegtli WC, Sturgis HL, Dizon FP, Vigers GP, Brandhuber BJ. PLoS One 5 e12913 (2010)
  3. International Union of Basic and Clinical Pharmacology. XC. multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands. Christopoulos A, Changeux JP, Catterall WA, Fabbro D, Burris TP, Cidlowski JA, Olsen RW, Peters JA, Neubig RR, Pin JP, Sexton PM, Kenakin TP, Ehlert FJ, Spedding M, Langmead CJ. Pharmacol Rev 66 918-947 (2014)
  4. Novel approaches for targeting kinases: allosteric inhibition, allosteric activation and pseudokinases. Cowan-Jacob SW, Jahnke W, Knapp S. Future Med Chem 6 541-561 (2014)
  5. Structure-based discovery of cellular-active allosteric inhibitors of FAK. Tomita N, Hayashi Y, Suzuki S, Oomori Y, Aramaki Y, Matsushita Y, Iwatani M, Iwata H, Okabe A, Awazu Y, Isono O, Skene RJ, Hosfield DJ, Miki H, Kawamoto T, Hori A, Baba A. Bioorg Med Chem Lett 23 1779-1785 (2013)
  6. DockBench: An Integrated Informatic Platform Bridging the Gap between the Robust Validation of Docking Protocols and Virtual Screening Simulations. Cuzzolin A, Sturlese M, Malvacio I, Ciancetta A, Moro S. Molecules 20 9977-9993 (2015)
  7. Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing. Reader JC, Matthews TP, Klair S, Cheung KM, Scanlon J, Proisy N, Addison G, Ellard J, Piton N, Taylor S, Cherry M, Fisher M, Boxall K, Burns S, Walton MI, Westwood IM, Hayes A, Eve P, Valenti M, de Haven Brandon A, Box G, van Montfort RL, Williams DH, Aherne GW, Raynaud FI, Eccles SA, Garrett MD, Collins I. J Med Chem 54 8328-8342 (2011)
  8. Allosteric p97 Inhibitors Can Overcome Resistance to ATP-Competitive p97 Inhibitors for Potential Anticancer Therapy. Wang F, Li S, Gan T, Stott GM, Flint A, Chou TF. ChemMedChem 15 685-694 (2020)
  9. Integrated one-flow synthesis of heterocyclic thioquinazolinones through serial microreactions with two organolithium intermediates. Kim H, Lee HJ, Kim DP. Angew Chem Int Ed Engl 54 1877-1880 (2015)
  10. Human kinome drug discovery and the emerging importance of atypical allosteric inhibitors. Eglen RM, Reisine T. Expert Opin Drug Discov 5 277-290 (2010)
  11. Development of WEE2 kinase inhibitors as novel non-hormonal female contraceptives that target meiosis†. Hanna CB, Mudaliar D, John K, Allen CL, Sun L, Hawkinson JE, Schönbrunn E, Georg GI, Jensen JT. Biol Reprod 103 368-377 (2020)
  12. Discovery of holoenzyme-disrupting chemicals as substrate-selective CK2 inhibitors. Kufareva I, Bestgen B, Brear P, Prudent R, Laudet B, Moucadel V, Ettaoussi M, Sautel CF, Krimm I, Engel M, Filhol O, Borgne ML, Lomberget T, Cochet C, Abagyan R. Sci Rep 9 15893 (2019)
  13. CHK1 kinase inhibition: identification of allosteric hits using MD simulations, pharmacophore modeling, docking and MM-PBSA calculations. Al-Shar'i N, Musleh SS. Mol Divers 26 903-921 (2022)
  14. Design, synthesis, and protein methyltransferase activity of a unique set of constrained amine containing compounds. Zhou H, Che X, Bao G, Wang N, Peng L, Barnash KD, Frye SV, James LI, Bai X. Bioorg Med Chem Lett 26 4436-4440 (2016)
  15. Docking-based 3D-QSAR study of pyridyl aminothiazole derivatives as checkpoint kinase 1 inhibitors. Balupuri A, Balasubramanian PK, Gadhe CG, Cho SJ. SAR QSAR Environ Res 25 651-671 (2014)
  16. Identification of novel inhibitors of human Chk1 using pharmacophore-based virtual screening and their evaluation as potential anti-cancer agents. Kumar V, Khan S, Gupta P, Rastogi N, Mishra DP, Ahmed S, Siddiqi MI. J Comput Aided Mol Des 28 1247-1256 (2014)
  17. Application of Deep Eutectic Solvents in the Synthesis of Substituted 2-Mercaptoquinazolin-4(3H)-Ones: A Comparison of Selected Green Chemistry Methods. Komar M, Kraljević TG, Jerković I, Molnar M. Molecules 27 558 (2022)
  18. Computational studies on the binding mechanism between triazolone inhibitors and Chk1 by molecular docking and molecular dynamics. Lv M, Ma S, Tian Y, Zhang X, Lv W, Zhai H. Mol Biosyst 11 275-286 (2015)
  19. Identification of highly selective type II kinase inhibitors with chiral peptidomimetic tails. Han SJ, Jung JE, Oh DH, Kim M, Kim JM, Chung KS, Han HS, Lee JH, Lee KT, Jeong HJ, Park IH, Jeon E, Shin JS, Hwang D, Cho AE, Lee DH, Sim T. J Enzyme Inhib Med Chem 37 1257-1277 (2022)


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