title: Structural Re-engineering of the α-Helix Mimetic JY-1-106 into Small Molecules: Disruption of the Mcl-1-Bak-BH3 Protein-Protein Interaction with 2,6-Di-Substituted Nicotinates.
abstract: The disruption of aberrant protein-protein interactions (PPIs) with synthetic agents remains a challenging goal in contemporary medicinal chemistry but some progress has been made. One such dysregulated PPI is that between the anti-apoptotic Bcl-2 proteins, including myeloid cell leukemia-1 (Mcl-1), and the α-helical Bcl-2 homology-3 (BH3) domains of its pro-apoptotic counterparts, such as Bak. Herein, we describe the discovery of small-molecule inhibitors of the Mcl-1 oncoprotein based on a novel chemotype. Particularly, re-engineering of our α-helix mimetic JY-1-106 into 2,6-di-substituted nicotinates afforded inhibitors of comparable potencies but with significantly decreased molecular weights. The most potent inhibitor 2-(benzyloxy)-6-(4-chloro-3,5-dimethylphenoxy)nicotinic acid (1 r: Ki =2.90 μm) likely binds in the p2 pocket of Mcl-1 and engages R263 in a salt bridge through its carboxylic acid, as supported by 2D (1) H-(15) N HSQC NMR data. Significantly, inhibitors were easily accessed in just four steps, which will facilitate future optimization efforts.
authors: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA.
authors: Brandon
authors: B
authors: Drennen
authors: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA.
authors: Jacob A
authors: JA
authors: Scheenstra
authors: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA.
authors: Jeremy L
authors: JL
authors: Yap
authors: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA.
authors: Lijia
authors: L
authors: Chen
authors: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA.
authors: Maryanna E
authors: ME
authors: Lanning
authors: Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
authors: Braden M
authors: BM
authors: Roth
authors: Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.|University of Maryland, Greenebaum Cancer Center, Baltimore, MD, 21201, USA.
authors: Paul T
authors: PT
authors: Wilder
authors: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA. sfletcher@rx.umaryland.edu.|University of Maryland, Greenebaum Cancer Center, Baltimore, MD, 21201, USA. sfletcher@rx.umaryland.edu.
authors: Steven
authors: S
authors: Fletcher
mesh_terms: D051023:BH3 Interacting Domain Death Agonist Protein / Q000737:chemistry / Q000378:metabolism*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000737:chemistry / Q000378:metabolism*; D009525:Niacin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding / Q000187:drug effects; D015202:Protein Engineering; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry / Q000378:metabolism*; D062366:para-Aminobenzoates / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C494772:BAK1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; D001549:Benzamides; C587245:JY-1-106; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D054852:Small Molecule Libraries; D050998:bcl-2 Homologous Antagonist-Killer Protein; D062366:para-Aminobenzoates; D009525:Niacin
keywords: JY-1-106; Mcl-1; cancer; nicotinic acid; protein-protein interactions