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Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors.

Medina JR, Becker CJ, Blackledge CW, Duquenne C, Feng Y, Grant SW, Heerding D, Li WH, Miller WH, Romeril SP, Scherzer D, Shu A, Bobko MA, Chadderton AR, Dumble M, Gardiner CM, Gilbert S, Liu Q, Rabindran SK, Sudakin V, Xiang H, Brady PG, Campobasso N, Ward P, Axten JM
J Med Chem 54 1871-95 (2011)
Related entries: 3qcq, 3qcx, 3qcy, 3qd0, 3qd3, 3qd4

Cited: 26 times
EuropePMC logo PMID: 21341675

Abstract

Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.

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  1. Design, Synthesis and Biological Activity Evaluation of S-Substituted 1H-5-Mercapto-1,2,4-Triazole Derivatives as Antiproliferative Agents in Colorectal Cancer. Mioc M, Avram S, Bercean V, Kurunczi L, Ghiulai RM, Oprean C, Coricovac DE, Dehelean C, Mioc A, Balan-Porcarasu M, Tatu C, Soica C. Front Chem 6 373 (2018)


Reviews citing this publication (4)

  1. PI3K signaling in cancer: beyond AKT. Lien EC, Dibble CC, Toker A. Curr. Opin. Cell Biol. 45 62-71 (2017)
  2. Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia. Carneiro BA, Kaplan JB, Altman JK, Giles FJ, Platanias LC. Cancer Biol. Ther. 16 648-656 (2015)
  3. PDK1 inhibitors. Barile E, De SK, Pellecchia M. Pharm Pat Anal 1 145-163 (2012)
  4. Protein Kinase Inhibitors as Therapeutic Drugs in AML: Advances and Challenges. Ling Y, Zhang Z, Zhang H, Huang Z. Curr. Pharm. Des. 23 4303-4310 (2017)

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  1. A public-private partnership to unlock the untargeted kinome. Knapp S, Arruda P, Blagg J, Burley S, Drewry DH, Edwards A, Fabbro D, Gillespie P, Gray NS, Kuster B, Lackey KE, Mazzafera P, Tomkinson NC, Willson TM, Workman P, Zuercher WJ. Nat. Chem. Biol. 9 3-6 (2013)
  2. Akt is efficiently activated by PIF-pocket- and PtdIns(3,4,5)P3-dependent mechanisms leading to resistance to PDK1 inhibitors. Najafov A, Shpiro N, Alessi DR. Biochem. J. 448 285-295 (2012)
  3. 3-phosphoinositide-dependent kinase 1 controls breast tumor growth in a kinase-dependent but Akt-independent manner. Gagliardi PA, di Blasio L, Orso F, Seano G, Sessa R, Taverna D, Bussolino F, Primo L. Neoplasia 14 719-731 (2012)
  4. Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer. Jansen VM, Bhola NE, Bauer JA, Formisano L, Lee KM, Hutchinson KE, Witkiewicz AK, Moore PD, Estrada MV, Sánchez V, Ericsson PG, Sanders ME, Pohlmann PR, Pishvaian MJ, Riddle DA, Dugger TC, Wei W, Knudsen ES, Arteaga CL. Cancer Res. 77 2488-2499 (2017)
  5. Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten(-/-) melanoma. Scortegagna M, Ruller C, Feng Y, Lazova R, Kluger H, Li JL, De SK, Rickert R, Pellecchia M, Bosenberg M, Ronai ZA. Oncogene 33 4330-4339 (2014)
  6. A small-molecule mimic of a peptide docking motif inhibits the protein kinase PDK1. Rettenmaier TJ, Sadowsky JD, Thomsen ND, Chen SC, Doak AK, Arkin MR, Wells JA. Proc. Natl. Acad. Sci. U.S.A. 111 18590-18595 (2014)
  7. Design of New Ligands for the Palladium-Catalyzed Arylation of α-Branched Secondary Amines. Park NH, Vinogradova EV, Surry DS, Buchwald SL. Angew Chem Int Ed Engl 54 8259-8262 (2015)
  8. Could MM-GBSA be accurate enough for calculation of absolute protein/ligand binding free energies? Mulakala C, Viswanadhan VN. J. Mol. Graph. Model. 46 41-51 (2013)
  9. Novel isoquinolone PDK1 inhibitors discovered through fragment-based lead discovery. Johnson MC, Hu Q, Lingardo L, Ferre RA, Greasley S, Yan J, Kath J, Chen P, Ermolieff J, Alton G. J Comput Aided Mol Des 25 689-698 (2011)
  10. An amino-indazole scaffold with spectrum selective kinase inhibition of FLT3, PDGFRα and kit. Deng X, Zhou W, Weisberg E, Wang J, Zhang J, Sasaki T, Nelson E, Griffin JD, Jänne PA, Gray NS. Bioorg. Med. Chem. Lett. 22 4579-4584 (2012)
  11. Discovery of novel 7-azaindoles as PDK1 inhibitors. Wucherer-Plietker M, Merkul E, Müller TJJ, Esdar C, Knöchel T, Heinrich T, Buchstaller HP, Greiner H, Dorsch D, Finsinger D, Calderini M, Bruge D, Grädler U. Bioorg. Med. Chem. Lett. 26 3073-3080 (2016)
  12. Serum can overcome contact inhibition in confluent human pulmonary artery smooth muscle cells. Solodushko V, Khader HA, Fouty BW. PLoS ONE 8 e71490 (2013)
  13. Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase. Volkov OA, Brockway AJ, Wring SA, Peel M, Chen Z, Phillips MA, De Brabander JK. J. Med. Chem. 61 1182-1203 (2018)
  14. Auto In Silico Ligand Directing Evolution to Facilitate the Rapid and Efficient Discovery of Drug Lead. Wu F, Zhuo L, Wang F, Huang W, Hao G, Yang G. iScience 23 101179 (2020)
  15. The 3-phosphoinositide-dependent protein kinase 1 is an essential upstream activator of protein kinase A in malaria parasites. Hitz E, Wiedemar N, Passecker A, Graça BAS, Scheurer C, Wittlin S, Brancucci NMB, Vakonakis I, Mäser P, Voss TS. PLoS Biol 19 e3001483 (2021)
  16. 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)
  17. Computer-Aided Drug Design (CADD) to De-Orphanize Marine Molecules: Finding Potential Therapeutic Agents for Neurodegenerative and Cardiovascular Diseases. Llorach-Pares L, Nonell-Canals A, Avila C, Sanchez-Martinez M. Mar Drugs 20 53 (2022)
  18. Exploration of piperidine 3D fragment chemical space: synthesis and 3D shape analysis of fragments derived from 20 regio- and diastereoisomers of methyl substituted pipecolinates. Jones SP, Firth JD, Wheldon MC, Atobe M, Hubbard RE, Blakemore DC, De Fusco C, Lucas SCC, Roughley SD, Vidler LR, Whatton MA, Woolford AJ, Wrigley GL, O'Brien P. RSC Med Chem 13 1614-1620 (2022)
  19. Selective inhibition of intestinal guanosine 3',5'-cyclic monophosphate signaling by small-molecule protein kinase inhibitors. Bijvelds MJC, Tresadern G, Hellemans A, Smans K, Nieuwenhuijze NDA, Meijsen KF, Bongartz JP, Ver Donck L, de Jonge HR, Schuurkes JAJ, De Maeyer JH. J. Biol. Chem. 293 8173-8181 (2018)
  20. Synthesis and Activity Evaluation of Nasopharyngeal Carcinoma Inhibitors Based on 6-(Pyrimidin-4-yl)-1H-indazole. Liao B, Peng L, Zhou J, Mo H, Zhao J, Yang Z, Guo X, Zhang P, Zhang X, Zhu Z. Chem Biodivers 16 e1800598 (2019)
  21. [Advances in leukemia inhibitors targeting PI3K/AKT/mTOR pathway]. Wang L, Chu Y, Cheng T, Yuan W. Zhonghua Xue Ye Xue Za Zhi 36 888-893 (2015)


Related citations provided by authors (1)

  1. Aminoindazole PDK1 Inhibitors: A Case Study in Fragment-Based Drug Discovery. Medina JR, Blackledge CW, Heerding DA, Campobasso N, Ward P, Briand J, Wright L, Axten JM ACS Med Chem Lett 1 439-442 (2010)

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