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Szlavik, Zoltan; Csekei, Marton; Paczal, Attila; Szabo, Zoltan B; Sipos, Szabolcs; Radics, Gabor; Proszenyak, Agnes; Balint, Balazs; Murray, James; Davidson, James; Chen, Ijen; Dokurno, Pawel; Surgenor, Allan E; Daniels, Zoe Marie; Hubbard, Roderick E; Le Toumelin-Braizat, Gaëtane; Claperon, Audrey; Lysiak-Auvity, Gaëlle; Girard, Anne-Marie; Bruno, Alain; Chanrion, Maia; Colland, Frédéric; Maragno, Ana-Leticia; Demarles, Didier; Geneste, Olivier; Kotschy, Andras
Journal of medicinal chemistry, 11/2020, Letnik: 63, Številka: 22Journal Article
Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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