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Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 1: design, synthesis and biological activity.

Islam I, Bryant J, Chou YL, Kochanny MJ, Lee W, Phillips GB, Yu H, Adler M, Whitlow M, Ho E, Lentz D, Polokoff MA, Subramanyam B, Wu JM, Zhu D, Feldman RI, Arnaiz DO
Bioorg Med Chem Lett 17 3814-8 (2007)
Related entries: 1z5m, 2pe0

Cited: 22 times
EuropePMC logo PMID: 17531483

Abstract

HTS screening identified 1 with micromolar inhibitory activity against PDK1. Optimization of 1 afforded 4i (BX-517) which has single-digit nanomolar activity against PDK1 and excellent selectivity against PKA.

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  1. Recipes for the selection of experimental protein conformations for virtual screening. Rueda M, Bottegoni G, Abagyan R. J Chem Inf Model 50 186-193 (2010)
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  1. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Garcia-Echeverria C, Sellers WR. Oncogene 27 5511-5526 (2008)
  2. Small-molecule inhibitors of PDK1. Peifer C, Alessi DR. ChemMedChem 3 1810-1838 (2008)
  3. PDK1 inhibitors. Barile E, De SK, Pellecchia M. Pharm Pat Anal 1 145-163 (2012)
  4. Target-Based Anticancer Indole Derivatives for the Development of Anti-Glioblastoma Agents. Salerno S, Barresi E, Baglini E, Poggetti V, Da Settimo F, Taliani S. Molecules 28 2587 (2023)

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  1. Genetic and pharmacological inhibition of PDK1 in cancer cells: characterization of a selective allosteric kinase inhibitor. Nagashima K, Shumway SD, Sathyanarayanan S, Chen AH, Dolinski B, Xu Y, Keilhack H, Nguyen T, Wiznerowicz M, Li L, Lutterbach BA, Chi A, Paweletz C, Allison T, Yan Y, Munshi SK, Klippel A, Kraus M, Bobkova EV, Deshmukh S, Xu Z, Mueller U, Szewczak AA, Pan BS, Richon V, Pollock R, Blume-Jensen P, Northrup A, Andersen JN. J. Biol. Chem. 286 6433-6448 (2011)
  2. Discovery of a potent and highly selective PDK1 inhibitor via fragment-based drug discovery. Erlanson DA, Arndt JW, Cancilla MT, Cao K, Elling RA, English N, Friedman J, Hansen SK, Hession C, Joseph I, Kumaravel G, Lee WC, Lind KE, McDowell RS, Miatkowski K, Nguyen C, Nguyen TB, Park S, Pathan N, Penny DM, Romanowski MJ, Scott D, Silvian L, Simmons RL, Tangonan BT, Yang W, Sun L. Bioorg. Med. Chem. Lett. 21 3078-3083 (2011)
  3. Using a Genetically Encoded Sensor to Identify Inhibitors of Toxoplasma gondii Ca2+ Signaling. Sidik SM, Hortua Triana MA, Paul AS, El Bakkouri M, Hackett CG, Tran F, Westwood NJ, Hui R, Zuercher WJ, Duraisingh MT, Moreno SN, Lourido S. J. Biol. Chem. 291 9566-9580 (2016)
  4. Benzo[c][2,7]naphthyridines as inhibitors of PDK-1. Kim KH, Wissner A, Floyd MB, Fraser HL, Wang YD, Dushin RG, Hu Y, Olland A, Guo B, Arndt K. Bioorg. Med. Chem. Lett. 19 5225-5228 (2009)
  5. Synthesis of Novel 3,5-Disubstituted-2-oxindole Derivatives As Antitumor Agents against Human Nonsmall Cell Lung Cancer. Nesi G, Sestito S, Mey V, Ricciardi S, Falasca M, Danesi R, Lapucci A, Breschi MC, Fogli S, Rapposelli S. ACS Med Chem Lett 4 1137-1141 (2013)
  6. 5-Hydroxy-7-azaindolin-2-one, a novel hybrid of pyridinol and sunitinib: design, synthesis and cytotoxicity against cancer cells. Shah S, Lee C, Choi H, Gautam J, Jang H, Kim GJ, Lee YJ, Chaudhary CL, Park SW, Nam TG, Kim JA, Jeong BS. Org. Biomol. Chem. 14 4829-4841 (2016)
  7. Locking PDK1 in DFG-out conformation through 2-oxo-indole containing molecules: Another tools to fight glioblastoma. Sestito S, Daniele S, Nesi G, Zappelli E, Di Maio D, Marinelli L, Digiacomo M, Lapucci A, Martini C, Novellino E, Rapposelli S. Eur J Med Chem 118 47-63 (2016)
  8. Structure-based design of PDK1 inhibitors. Poulsen A, Blanchard S, Soh CK, Lee C, Williams M, Wang H, Dymock B. Bioorg. Med. Chem. Lett. 22 305-307 (2012)
  9. Synthesis and antitumor activity of 5-(5-halogenated-2-oxo-1H-pyrrolo[2,3-b]pyridin-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamides. Wang M, Ye C, Liu M, Wu Z, Li L, Wang C, Liu X, Guo H. Bioorg. Med. Chem. Lett. 25 2782-2787 (2015)
  10. Structure-based CoMFA and CoMSIA study of indolinone inhibitors of PDK1. Kaur K, Talele TT. J. Comput. Aided Mol. Des. 23 25-36 (2009)
  11. Leishmania parasitophorous vacuole membranes display phosphoinositides that create conditions for continuous Akt activation and a target for miltefosine in Leishmania infections. Zhang N, Prasad S, Huyghues Despointes CE, Young J, Kima PE. Cell. Microbiol. 20 e12889 (2018)
  12. Synthesis and Antitumor Activity of 5-Bromo-7-azaindolin-2-one Derivatives Containing a 2,4-Dimethyl-1H-pyrrole-3-carboxamide Moiety. Zhang J, Shen W, Li X, Chai Y, Li S, Lv K, Guo H, Liu M. Molecules 21 (2016)
  13. Applying conformational selection theory to improve crossdocking efficiency in 3-phosphoinositide dependent protein kinase-1. Kotasthane A, Mulakala C, Viswanadhan VN. Proteins 82 436-451 (2014)


Related citations provided by authors (3)

  1. Indolinone based Phhosphoinositide-Dependent Kinase-1 (PDK1) inhibitors- Part 2: Optimization of BX-517. Islam I, Brown G, Bryant J, Hrvatin P, Kochanny MJ, Phillips GB, Yuan S, Adler M, Whitlow M, Lentz D, Polokoff MA, Wu J, Shen J, Walters J, Ho E, Subramanyam B, Zhu D, Feldman RI, Arnaiz DO To be Published - (2007)
  2. Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1.. Feldman RI, Wu JM, Polokoff MA, Kochanny MJ, Dinter H, Zhu D, Biroc SL, Alicke B, Bryant J, Yuan S, Buckman BO, Lentz D, Ferrer M, Whitlow M, Adler M, Finster S, Chang Z, Arnaiz DO J Biol Chem 280 19867-74 (2005)
  3. High Resolution Crystal Structure of the Human Pdk1 Catalytic Domain Defines the Regulatory Phosphopeptide Docking Site.. Biondi RM, Komander D, Thomas CC, Lizcano JM, Deak M, Alessi DR, Van Aalten DMF EMBO J. 21 4219-4228 (2002)

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