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Design and synthesis of novel macrocyclic 2-amino-6-arylpyrimidine Hsp90 inhibitors.

Suda A, Koyano H, Hayase T, Hada K, Kawasaki K, Komiyama S, Hasegawa K, Fukami TA, Sato S, Miura T, Ono N, Yamazaki T, Saitoh R, Shimma N, Shiratori Y, Tsukuda T
Bioorg Med Chem Lett 22 1136-41 (2012)
Related entries: 3vha, 3vhc

Cited: 10 times
EuropePMC logo PMID: 22192591

Abstract

Macrocyclic compounds bearing a 2-amino-6-arylpyrimidine moiety were identified as potent heat shock protein 90 (Hsp90) inhibitors by modification of 2-amino-6-aryltriazine derivative (CH5015765). We employed a macrocyclic structure as a skeleton of new inhibitors to mimic the geldanamycin-Hsp90 interactions. Among the identified inhibitors, CH5164840 showed high binding affinity for N-terminal Hsp90α (K(d)=0.52nM) and strong anti-proliferative activity against human cancer cell lines (HCT116 IC(50)=0.15μM, NCI-N87 IC(50)=0.066μM). CH5164840 displayed high oral bioavailability in mice (F=70.8%) and potent antitumor efficacy in a HCT116 human colorectal cancer xenograft model (tumor growth inhibition=83%).

Articles - 3vhd mentioned but not cited (1)

  1. Machine learning accelerates MD-based binding pose prediction between ligands and proteins. Terayama K, Iwata H, Araki M, Okuno Y, Tsuda K. Bioinformatics 34 770-778 (2018)


Reviews citing this publication (5)

  1. Targeting protein-protein interactions as an anticancer strategy. Ivanov AA, Khuri FR, Fu H. Trends Pharmacol Sci 34 393-400 (2013)
  2. Chaperome heterogeneity and its implications for cancer study and treatment. Wang T, Rodina A, Dunphy MP, Corben A, Modi S, Guzman ML, Gewirth DT, Chiosis G. J Biol Chem 294 2162-2179 (2019)
  3. HSP90 inhibitors and cancer: Prospects for use in targeted therapies (Review). Li ZN, Luo Y. Oncol Rep 49 6 (2023)
  4. An Insight into the Medicinal Chemistry Perspective of Macrocyclic Derivatives with Antitumor Activity: A Systematic Review. Liang Y, Fang R, Rao Q. Molecules 27 2837 (2022)
  5. Heterocyclic Compounds as Hsp90 Inhibitors: A Perspective on Anticancer Applications. Ardestani M, Khorsandi Z, Keshavarzipour F, Iravani S, Sadeghi-Aliabadi H, Varma RS. Pharmaceutics 14 2220 (2022)

Articles citing this publication (4)

  1. Enhanced antitumor activity of erlotinib in combination with the Hsp90 inhibitor CH5164840 against non-small-cell lung cancer. Ono N, Yamazaki T, Tsukaguchi T, Fujii T, Sakata K, Suda A, Tsukuda T, Mio T, Ishii N, Kondoh O, Aoki Y. Cancer Sci 104 1346-1352 (2013)
  2. Binding-affinity predictions of HSP90 in the D3R Grand Challenge 2015 with docking, MM/GBSA, QM/MM, and free-energy simulations. Misini Ignjatović M, Caldararu O, Dong G, Muñoz-Gutierrez C, Adasme-Carreño F, Ryde U. J Comput Aided Mol Des 30 707-730 (2016)
  3. Computational Macrocyclization: From de novo Macrocycle Generation to Binding Affinity Estimation. Wagner V, Jantz L, Briem H, Sommer K, Rarey M, Christ CD. ChemMedChem 12 1866-1872 (2017)
  4. Scaffold Hopping Transformations Using Auxiliary Restraints for Calculating Accurate Relative Binding Free Energies. Zou J, Li Z, Liu S, Peng C, Fang D, Wan X, Lin Z, Lee TS, Raleigh DP, Yang M, Simmerling C. J Chem Theory Comput 17 3710-3726 (2021)


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