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Structure-Guided Design of Group I Selective p21-Activated Kinase Inhibitors.

Crawford JJ, Lee W, Aliagas I, Mathieu S, Hoeflich KP, Zhou W, Wang W, Rouge L, Murray L, La H, Liu N, Fan PW, Cheong J, Heise CE, Ramaswamy S, Mintzer R, Liu Y, Chao Q, Rudolph J
J Med Chem 58 5121-36 (2015)
Related entries: 4zy5, 4zy6, 5bms

Cited: 13 times
EuropePMC logo PMID: 26030457

Abstract

The p21-activated kinases (PAKs) play important roles in cytoskeletal organization, cellular morphogenesis, and survival and have generated significant attention as potential therapeutic targets for cancer. Following a high-throughput screen, we identified an aminopyrazole scaffold-based series that was optimized to yield group I selective PAK inhibitors. A structure-based design effort aimed at targeting the ribose pocket for both potency and selectivity led to much-improved group I vs II selectivity. Early lead compounds contained a basic primary amine, which was found to be a major metabolic soft spot with in vivo clearance proceeding predominantly via N-acetylation. We succeeded in identifying replacements with improved metabolic stability, leading to compounds with lower in vivo rodent clearance and excellent group I PAK selectivity.

Articles - 4zy4 mentioned but not cited (2)

  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. 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 (3)

  1. P21-Activated Kinase 1: Emerging biological functions and potential therapeutic targets in Cancer. Yao D, Li C, Rajoka MSR, He Z, Huang J, Wang J, Zhang J. Theranostics 10 9741-9766 (2020)
  2. Recent advances on development of p21-activated kinase 4 inhibitors as anti-tumor agents. Li Y, Lu Q, Xie C, Yu Y, Zhang A. Front Pharmacol 13 956220 (2022)
  3. 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 (8)

  1. Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pK a Polar Moiety. Ndubaku CO, Crawford JJ, Drobnick J, Aliagas I, Campbell D, Dong P, Dornan LM, Duron S, Epler J, Gazzard L, Heise CE, Hoeflich KP, Jakubiak D, La H, Lee W, Lin B, Lyssikatos JP, Maksimoska J, Marmorstein R, Murray LJ, O'Brien T, Oh A, Ramaswamy S, Wang W, Zhao X, Zhong Y, Blackwood E, Rudolph J. ACS Med Chem Lett 6 1241-1246 (2015)
  2. PAK4 crystal structures suggest unusual kinase conformational movements. Zhang EY, Ha BH, Boggon TJ. Biochim Biophys Acta Proteins Proteom 1866 356-365 (2018)
  3. Prenylated quinolinecarboxylic acid derivative suppresses immune response through inhibition of PAK2. Ogura M, Kikuchi H, Suzuki T, Yamaki J, Homma MK, Oshima Y, Homma Y. Biochem Pharmacol 105 55-65 (2016)
  4. Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells. Song P, Zhao F, Li D, Qu J, Yao M, Su Y, Wang H, Zhou M, Wang Y, Gao Y, Li F, Zhao D, Zhang F, Rao Y, Xia M, Li H, Wang J, Cheng M. Acta Pharm Sin B 12 2905-2922 (2022)
  5. 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)
  6. Identification of Pak1 inhibitors using water thermodynamic analysis. Biswal J, Jayaprakash P, Suresh Kumar R, Venkatraman G, Poopandi S, Rangasamy R, Jeyaraman J. J Biomol Struct Dyn 38 13-31 (2020)
  7. Rate-Determining and Rate-Limiting Steps in the Clearance and Excretion of a Potent and Selective p21-Activated Kinase Inhibitor: A Case Study of Rapid Hepatic Uptake and Slow Elimination in Rat. Fan PW, Chen JZ, Allan Jaochico M, La H, Liu N, Mulder T, Cass RT, Durk M, Messick K, Valle N, Liu S, Lee W, Crawford JJ, Rudolf J, Murray LJ, Cyrus Khojasteh S, Wright M. Drug Metab Lett 10 91-100 (2016)
  8. 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)


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