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Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor.

Karpov AS, Amiri P, Bellamacina C, Bellance MH, Breitenstein W, Daniel D, Denay R, Fabbro D, Fernandez C, Galuba I, Guerro-Lagasse S, Gutmann S, Hinh L, Jahnke W, Klopp J, Lai A, Lindvall MK, Ma S, Möbitz H, Pecchi S, Rummel G, Shoemaker K, Trappe J, Voliva C, Cowan-Jacob SW, Marzinzik AL
ACS Med Chem Lett 6 776-81 (2015)
Related entries: 4zjj, 4zlo

Cited: 39 times
EuropePMC logo PMID: 26191365

Abstract

The discovery of inhibitors targeting novel allosteric kinase sites is very challenging. Such compounds, however, once identified could offer exquisite levels of selectivity across the kinome. Herein we report our structure-based optimization strategy of a dibenzodiazepine hit 1, discovered in a fragment-based screen, yielding highly potent and selective inhibitors of PAK1 such as 2 and 3. Compound 2 was cocrystallized with PAK1 to confirm binding to an allosteric site and to reveal novel key interactions. Compound 3 modulated PAK1 at the cellular level and due to its selectivity enabled valuable research to interrogate biological functions of the PAK1 kinase.

Articles - 4zji mentioned but not cited (5)

  1. Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases. Xu Q, Malecka KL, Fink L, Jordan EJ, Duffy E, Kolander S, Peterson JR, Dunbrack RL. Sci Signal 8 rs13 (2015)
  2. 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)
  3. Development and Utility of a PAK1-Selective Degrader. Chow HY, Karchugina S, Groendyke BJ, Toenjes S, Hatcher J, Donovan KA, Fischer ES, Abalakov G, Faezov B, Dunbrack R, Gray NS, Chernoff J. J Med Chem 65 15627-15641 (2022)
  4. Kinome-Wide Profiling Identifies Human WNK3 as a Target of Cajanin Stilbene Acid from Cajanus cajan (L.) Millsp. Özenver N, Kadioglu O, Fu Y, Efferth T. Int J Mol Sci 23 1506 (2022)
  5. Molecular modelling approaches predicted 1,2,3-triazolyl ester of ketorolac (15K) to be a novel allosteric modulator of the oncogenic kinase PAK1. Shahinozzaman M, Ahmed S, Emran R, Tawata S. Sci Rep 11 17471 (2021)


Reviews citing this publication (11)

  1. Trends in kinase drug discovery: targets, indications and inhibitor design. Attwood MM, Fabbro D, Sokolov AV, Knapp S, Schiöth HB. Nat Rev Drug Discov 20 839-861 (2021)
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  4. Regulating Cdc42 and Its Signaling Pathways in Cancer: Small Molecules and MicroRNA as New Treatment Candidates. Xiao XH, Lv LC, Duan J, Wu YM, He SJ, Hu ZZ, Xiong LX. Molecules 23 E787 (2018)
  5. Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors. Arter C, Trask L, Ward S, Yeoh S, Bayliss R. J Biol Chem 298 102247 (2022)
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  7. The protein kinase CK1: Inhibition, activation, and possible allosteric modulation. Sunkari YK, Meijer L, Flajolet M. Front Mol Biosci 9 916232 (2022)
  8. 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)
  9. Group I PAKs in myelin formation and repair of the central nervous system: what, when, and how. Wang Y, Guo F. Biol Rev Camb Philos Soc 97 615-639 (2022)
  10. PAK1 and Therapy Resistance in Melanoma. Kichina JV, Maslov A, Kandel ES. Cells 12 2373 (2023)
  11. Targeting P21-Activated Kinase-1 for Metastatic Prostate Cancer. Somanath PR, Chernoff J, Cummings BS, Prasad SM, Homan HD. Cancers (Basel) 15 2236 (2023)

Articles citing this publication (23)

  1. Dynamic 3D proteomes reveal protein functional alterations at high resolution in situ. Cappelletti V, Hauser T, Piazza I, Pepelnjak M, Malinovska L, Fuhrer T, Li Y, Dörig C, Boersema P, Gillet L, Grossbach J, Dugourd A, Saez-Rodriguez J, Beyer A, Zamboni N, Caflisch A, de Souza N, Picotti P. Cell 184 545-559.e22 (2021)
  2. Combined inhibition of Aurora A and p21-activated kinase 1 as a new treatment strategy in breast cancer. Korobeynikov V, Borakove M, Feng Y, Wuest WM, Koval AB, Nikonova AS, Serebriiskii I, Chernoff J, Borges VF, Golemis EA, Shagisultanova E. Breast Cancer Res Treat 177 369-382 (2019)
  3. Ponatinib (AP24534) inhibits MEKK3-KLF signaling and prevents formation and progression of cerebral cavernous malformations. Choi JP, Wang R, Yang X, Wang X, Wang L, Ting KK, Foley M, Cogger V, Yang Z, Liu F, Han Z, Liu R, Baell J, Zheng X. Sci Adv 4 eaau0731 (2018)
  4. De novo variants in PAK1 lead to intellectual disability with macrocephaly and seizures. Horn S, Au M, Basel-Salmon L, Bayrak-Toydemir P, Chapin A, Cohen L, Elting MW, Graham JM, Gonzaga-Jauregui C, Konen O, Holzer M, Lemke J, Miller CE, Rey LK, Wolf NI, Weiss MM, Waisfisz Q, Mirzaa GM, Wieczorek D, Sticht H, Abou Jamra R. Brain 142 3351-3359 (2019)
  5. Discovery and Optimization of Dibenzodiazepinones as Allosteric Mutant-Selective EGFR Inhibitors. De Clercq DJH, Heppner DE, To C, Jang J, Park E, Yun CH, Mushajiang M, Shin BH, Gero TW, Scott DA, Jänne PA, Eck MJ, Gray NS. ACS Med Chem Lett 10 1549-1553 (2019)
  6. Targeting group I p21-activated kinases to control malignant peripheral nerve sheath tumor growth and metastasis. Semenova G, Stepanova DS, Dubyk C, Handorf E, Deyev SM, Lazar AJ, Chernoff J. Oncogene 36 5421-5431 (2017)
  7. Impact of Allosteric Modulation in Drug Discovery: Innovation in Emerging Chemical Modalities. Han B, Salituro FG, Blanco MJ. ACS Med Chem Lett 11 1810-1819 (2020)
  8. Identification of a novel PAK1 inhibitor to treat pancreatic cancer. Wang J, Zhu Y, Chen J, Yang Y, Zhu L, Zhao J, Yang Y, Cai X, Hu C, Rosell R, Sun X, Cao P. Acta Pharm Sin B 10 603-614 (2020)
  9. PAK1 Positively Regulates Oligodendrocyte Morphology and Myelination. Brown TL, Hashimoto H, Finseth LT, Wood TL, Macklin WB. J Neurosci 41 1864-1877 (2021)
  10. PAK1 inhibitor IPA-3 mitigates metastatic prostate cancer-induced bone remodeling. Verma A, Artham S, Alwhaibi A, Adil MS, Cummings BS, Somanath PR. Biochem Pharmacol 177 113943 (2020)
  11. Solution structures and biophysical analysis of full-length group A PAKs reveal they are monomeric and auto-inhibited in cis. Sorrell FJ, Kilian LM, Elkins JM. Biochem J 476 1037-1051 (2019)
  12. Nuplazid suppresses esophageal squamous cell carcinoma growth in vitro and in vivo by targeting PAK4. Wei Y, Wu W, Jiang Y, Zhou H, Yu Y, Zhao L, Wu X, Lu X, Yuan Q, Wang Z, Dong Z, He L, Zhao J, Liu K. Br J Cancer 126 1037-1046 (2022)
  13. The Group I Pak inhibitor Frax-1036 sensitizes 11q13-amplified ovarian cancer cells to the cytotoxic effects of Rottlerin. Prudnikova TY, Chernoff J. Small GTPases 8 193-198 (2017)
  14. Cytotoxic Desulfated Saponin from Holothuria atra Predicted to Have High Binding Affinity to the Oncogenic Kinase PAK1: A Combined In Vitro and In Silico Study. Shahinozzaman M, Ishii T, Takano R, Halim MA, Hossain MA, Tawata S. Sci Pharm 86 E32 (2018)
  15. Data-Driven Exploration of Selectivity and Off-Target Activities of Designated Chemical Probes. Miljković F, Bajorath J. Molecules 23 E2434 (2018)
  16. PAK1 inhibition reduces tumor size and extends the lifespan of mice in a genetically engineered mouse model of Neurofibromatosis Type 2 (NF2). Hawley E, Gehlhausen J, Karchugina S, Chow HY, Araiza-Olivera D, Radu M, Smith A, Burks C, Jiang L, Li X, Bessler W, Masters A, Edwards D, Burgin C, Jones D, Yates C, Clapp DW, Chernoff J, Park SJ. Hum Mol Genet 30 1607-1617 (2021)
  17. Sterically stabilized liposomes targeting P21 (RAC1) activated kinase-1 and secreted phospholipase A2 suppress prostate cancer growth and metastasis. Verma A, Najahi-Missaoui W, Cummings BS, Somanath PR. Oncol Lett 20 179 (2020)
  18. Phosphorylation-dependent activity-based conformational changes in P21-activated kinase family members and screening of novel ATP competitive inhibitors. Gul M, Fakhar M, Najumuddin, Rashid S. PLoS One 14 e0225132 (2019)
  19. Proximity proteomics identifies septins and PAK2 as decisive regulators of actomyosin-mediated expulsion of von Willebrand factor. El-Mansi S, Robinson CL, Kostelnik KB, McCormack JJ, Mitchell TP, Lobato-Márquez D, Rajeeve V, Cutillas P, Cutler DF, Mostowy S, Nightingale TD. Blood 141 930-944 (2023)
  20. Targeting p21 activated kinase 1 (Pak1) to PAKup Pancreatic Cancer. Jagadeeshan S, Venkatraman G, Rayala SK. Expert Opin Ther Targets 20 1283-1285 (2016)
  21. Neuroprotective Effects of 2-Substituted 1, 3-Selenazole Amide Derivatives on Amyloid-Beta-Induced Toxicity in a Transgenic Caenorhabditis Elegans Model of Alzheimer's Disease. Wang H, Yue Y, Zhao H, Wu H, Jiang K, Li S, Zhao M, Lin F. Neurotox Res 39 841-850 (2021)
  22. Design, synthesis and biological evaluation of novel tetrahydrothieno [2,3-c]pyridine substitued benzoyl thiourea derivatives as PAK1 inhibitors in triple negative breast cancer. Yao D, Huang J, Wang J, He Z, Zhang J. J Enzyme Inhib Med Chem 35 1524-1538 (2020)
  23. Pak1 pathway hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer. Belli S, Esposito D, Allotta A, Servetto A, Ciciola P, Pesapane A, Ascione CM, Napolitano F, Di Mauro C, Vigliar E, Iaccarino A, De Angelis C, Bianco R, Formisano L. NPJ Breast Cancer 9 48 (2023)


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