2. Academic Validation
  3. Macrocyclic Carbon-Linked Pyrazoles As Novel Inhibitors of MCL-1

Macrocyclic Carbon-Linked Pyrazoles As Novel Inhibitors of MCL-1

  • ACS Med Chem Lett. 2023 Jul 3;14(7):955-961. doi: 10.1021/acsmedchemlett.3c00141.
Samuël Demin 1,  Aldo Peschiulli 1,  Adriana I Velter 1,  Ann Vos 1,  Benoît De Boeck 1,  Bradley Miller 2,  Frederik J R Rombouts 1,  Tristan Reuillon 1,  William Lento 2,  Maria Dominguez Blanco 1,  Matthieu Jouffroy 3,  Helena Steyvers 1,  Mariette Bekkers 1,  Cristina Altrocchi 1,  Beth Pietrak 2,  Seong Joo Koo 1,  Lawrence Szewczuk 2,  Ricardo Attar 2,  Ulrike Philippar 1
Affiliations

Affiliations

  • 1 Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, Beerse B-2340, Belgium.
  • 2 Janssen Research & Development LLC, 1400 McKean Road (Welsh Road), Spring House, Pennsylvania 19477, United States.
  • 3 Chemical Process R&D, Discovery Process Research, Janssen Pharmaceutica N.V., Beerse B-2340, Belgium.
PMID: 37465311 DOI: 10.1021/acsmedchemlett.3c00141
Abstract

Myeloid cell leukemia-1 (Mcl-1) is a member of the antiapoptotic Bcl-2 proteins family and a key regulator of mitochondrial homeostasis. Overexpression of Mcl-1 is found in many Cancer cells and contributes to tumor progression, which makes it an attractive therapeutic target. Pursuing our previous study of macrocyclic indoles for the inhibition of Mcl-1, we report herein the impact of both pyrazole and indole isomerism on the potency and overall properties of this family of compounds. We demonstrated that the incorporation of a fluorine atom on the naphthalene moiety was a necessary step to improve cellular potency and that, combined with the introduction of various side chains on the pyrazole, it enhanced solubility significantly. This exploration culminated in the discovery of compounds (Ra)-10 and (Ra)-15, possessing remarkable cellular potency and properties.

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