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42. Novel fluorinated carbonic anhydrase IX inhibitors reduce hypoxia-induced acidification and clonogenic survival of cancer cells

Author

Kazokaite, J., Kazokaite, J., Niemans, Raymon, Dudutiene, V., Becker, Holger M., Leitans, J., Zubriene, A., Baranauskiene, L., Gondi, Gabor, Zeidler, Reinhard, Matuliene, J., Tars, K., Yaromina, Ala, Lambin, Philippe, Dubois, Ludwig, Matulis, D., Kazokaite, J., Kazokaite, J., Niemans, Raymon, Dudutiene, V., Becker, Holger M., Leitans, J., Zubriene, A., Baranauskiene, L., Gondi, Gabor, Zeidler, Reinhard, Matuliene, J., Tars, K., Yaromina, Ala, Lambin, Philippe, Dubois, Ludwig, and Matulis, D.

Abstract

Human carbonic anhydrase (CA) IX has emerged as a promising anticancer target and a diagnostic biomarker for solid hypoxic tumors. Novel fluorinated CA IX inhibitors exhibited up to 50 pM affinity towards the recombinant human CA IX, selectivity over other CAs, and direct binding to Zn(II) in the active site of CA IX inducing novel conformational changes as determined by X-ray crystallography. Mass spectrometric gas-analysis confirmed the CA IX-based mechanism of the inhibitors in a CRISPR/Cas9-mediated CA IX knockout in HeLa cells. Hypoxia-induced extracellular acidification was significantly reduced in HeLa, H460, MDA-MB-231, and A549 cells exposed to the compounds, with the IC50 values up to 1.29 nM. A decreased clonogenic survival was observed when hypoxic H460 3D spheroids were incubated with our lead compound. These novel compounds are therefore promising agents for CA IXspecific therapy.

Published
2018

43. Target highlights from the first post-PSI CASP experiment (CASP12, May-August 2016)

Author

Kryshtafovych, A, Albrecht, R, Baslé, A, Bule, P, Caputo, A, Carvalho, A, Chao, K, Diskin, R, Fidelis, K, Fontes, C, Fredslund, F, Gilbert, H, Goulding, C, Hartmann, M, Hayes, C, Herzberg, O, Hill, J, Joachimiak, A, Kohring, G, Koning, R, Lo Leggio, L, Mangiagalli, M, Michalska, K, Moult, J, Najmudin, S, Nardini, M, Nardone, V, Ndeh, D, Nguyen, T, Pintacuda, G, Postel, S, Van Raaij, M, Roversi, P, Shimon, A, Singh, A, Sundberg, E, Tars, K, Zitzmann, N, Schwede, T, Kryshtafovych, A, Albrecht, R, Baslé, A, Bule, P, Caputo, A, Carvalho, A, Chao, K, Diskin, R, Fidelis, K, Fontes, C, Fredslund, F, Gilbert, H, Goulding, C, Hartmann, M, Hayes, C, Herzberg, O, Hill, J, Joachimiak, A, Kohring, G, Koning, R, Lo Leggio, L, Mangiagalli, M, Michalska, K, Moult, J, Najmudin, S, Nardini, M, Nardone, V, Ndeh, D, Nguyen, T, Pintacuda, G, Postel, S, Van Raaij, M, Roversi, P, Shimon, A, Singh, A, Sundberg, E, Tars, K, Zitzmann, N, and Schwede, T

Abstract

The functional and biological significance of the selected CASP12 targets are described by the authors of the structures. The crystallographers discuss the most interesting structural features of the target proteins and assess whether these features were correctly reproduced in the predictions submitted to the CASP12 experiment

Published
2018

44. Human carnitine biosynthesis proceeds via (2S,3S)-3-hydroxy-N(ε)-trimethyllysine

Author

Leśniak, RK, Markolovic, S, Tars, K, and Schofield, C

Abstract

N(ε)-Trimethyllysine hydroxylase (TMLH) catalyses the first step in mammalian biosynthesis of carnitine, which plays a crucial role in fatty acid metabolism. The stereochemistry of the 3-hydroxy-N(ε)-trimethyllysine product of TMLH has not been defined. We report enzymatic and asymmetric synthetic studies, which define the product of TMLH catalysis as (2S,3S)-3-hydroxy-N(ε)-trimethyllysine.

Published
2017
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