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NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family.

Tröster A, Heinzlmeir S, Berger BT, Gande SL, Saxena K, Sreeramulu S, Linhard V, Nasiri AH, Bolte M, Müller S, Kuster B, Médard G, Kudlinzki D, Schwalbe H
ChemMedChem 13 1629-1633 (2018)
Related entries: 6fnf, 6fng, 6fnh, 6fni, 6fnj, 6fnk, 6fnm

Cited: 10 times
EuropePMC logo PMID: 29928781

Abstract

Erythropoietin-producing hepatocellular (EPH) receptors are transmembrane receptor tyrosine kinases. Their extracellular domains bind specifically to ephrin A/B ligands, and this binding modulates intracellular kinase activity. EPHs are key players in bidirectional intercellular signaling, controlling cell morphology, adhesion, and migration. They are increasingly recognized as cancer drug targets. We analyzed the binding of NVP-BHG712 (NVP) to EPHA2 and EPHB4. Unexpectedly, all tested commercially available NVP samples turned out to be a regioisomer (NVPiso) of the inhibitor, initially described in a Novartis patent application. They only differ by the localization of a single methyl group on either one of two adjacent nitrogen atoms. The two compounds of identical mass revealed different binding modes. Furthermore, both in vitro and in vivo experiments showed that the isomers differ in their kinase affinity and selectivity.

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Reviews citing this publication (2)

  1. EphrinB2-EphB4 Signaling in Neurooncological Disease. Piffko A, Uhl C, Vajkoczy P, Czabanka M, Broggini T. Int J Mol Sci 23 1679 (2022)
  2. Eph receptors and ephrins in cancer progression. Pasquale EB. Nat Rev Cancer 24 5-27 (2024)

Articles citing this publication (7)

  1. Identification of molecular targets for the targeted treatment of gastric cancer using dasatinib. Montenegro RC, Howarth A, Ceroni A, Fedele V, Farran B, Mesquita FP, Frejno M, Berger BT, Heinzlmeir S, Sailem HZ, Tesch R, Ebner D, Knapp S, Burbano R, Kuster B, Müller S. Oncotarget 11 535-549 (2020)
  2. Integrated bioinformatics and statistical approaches to explore molecular biomarkers for breast cancer diagnosis, prognosis and therapies. Alam MS, Sultana A, Reza MS, Amanullah M, Kabir SR, Mollah MNH. PLoS One 17 e0268967 (2022)
  3. Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma. DiPrima M, Wang D, Tröster A, Maric D, Terrades-Garcia N, Ha T, Kwak H, Sanchez-Martin D, Kudlinzki D, Schwalbe H, Tosato G. Mol Oncol 13 2441-2459 (2019)
  4. COE Inhibits Vasculogenic Mimicry by Targeting EphA2 in Hepatocellular Carcinoma, a Research Based on Proteomics Analysis. Chu Z, Shi X, Chen G, He X, Qian Y, Wang H, Tao L, Liu Y, Jiang W, Chen J. Front Pharmacol 12 619732 (2021)
  5. Sterile α-motif domain requirement for cellular signaling and survival. Ray S, Chee L, Matson DR, Palermo NY, Bresnick EH, Hewitt KJ. J Biol Chem 295 7113-7125 (2020)
  6. Optimization of the Lead Compound NVP-BHG712 as a Colorectal Cancer Inhibitor. Tröster A, DiPrima M, Jores N, Kudlinzki D, Sreeramulu S, Gande SL, Linhard V, Ludig D, Schug A, Saxena K, Reinecke M, Heinzlmeir S, Leisegang MS, Wollenhaupt J, Lennartz F, Weiss MS, Kuster B, Tosato G, Schwalbe H. Chemistry 29 e202203967 (2023)
  7. The Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitor NVP-BHG712: Effects of Regioisomers on Tumor Growth, Perfusion, and Hypoxia in EphB4-Positive A375 Melanoma Xenografts. Neuber C, Tröster A, Löser R, Belter B, Schwalbe H, Pietzsch J. Molecules 25 E5115 (2020)


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