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Hekking, Koen F. W.; Maroto, Sergio; van Kekem, Kees; Haasjes, Frank S.; Slootweg, Jack C.; Oude Alink, Patrick G. B.; Dirks, Ron; Sardana, Malvika; Bolster, Marjon G.; Kuijpers, Brian; Smith, Dennis; Doodeman, Robin; Scheepstra, Marcel; Zech, Birgit; Mulvihill, Mark; Renzetti, Louis M.; Babiss, Lee; Centrella, Paolo A.; Clark, Matthew A.; Cuozzo, John W.; Guié, Marie-Aude; Sigel, Eric; Habeshian, Sevan; Hupp, Christopher D.; Liu, Julie; Thomson, Heather A.; Zhang, Ying; Keefe, Anthony D.; Müller, Gerhard; Gremmen, Stijn
Journal of medicinal chemistry, 02/2024, Letnik: 67, Številka: 4Journal Article
Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein–protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitro potency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57/59 with a balanced profile, which are suitable for future development toward therapeutic use.
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Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
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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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