- Discovery of MK-4688: An Efficient Inhibitor of the HDM2-p53 Protein-Protein Interaction
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Identification of low-dose, low-molecular-weight, drug-like inhibitors of protein-protein interactions (PPIs) is a challenging area of research. Despite the challenges, the therapeutic potential of PPI inhibition has driven significant efforts toward this goal. Adding to recent success in this area, we describe herein our efforts to optimize a novel purine carboxylic acid-derived inhibitor of the HDM2-p53 PPI into a series of low-projected dose inhibitors with overall favorable pharmacokinetic and physical properties. Ultimately, a strategy focused on leveraging known binding hot spots coupled with biostructural information to guide the design of conformationally constrained analogs and a focus on efficiency metrics led to the discovery of MK-4688 (compound 56), a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.
- Altman, Michael D.,Bogen, Stephane,Cai, Mingmei,Cammarano, Carolyn,Chen, Dapeng,Christopher, Matthew,Cryan, John,Daublain, Pierre,Dussault, Isabelle,Fradera, Xavier,Geda, Prasanthi,Goldenblatt, Peter,Hill, Armetta D.,Kemper, Raymond A.,Kutilek, Victoria,Li, Chaomin,Machacek, Michelle R.,Marshall, C. Gary,Martinez, Michelle,McCoy, Mark,Nair, Latha,Pan, Weidong,Reutershan, Michael H.,Scapin, Giovanna,Shizuka, Manami,Spatz, Marianne L.,Steinhuebel, Dietrich,Sun, Binyuan,Thompson, Christopher F.,Trotter, B. Wesley,Voss, Matthew E.,Wang, Xiao,Yang, Liping,Yeh, Tammie C.
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p. 16213 - 16241
(2021/11/16)
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- N-Acyl-N'-(pyridin-2-yl) Ureas and Analogs Exhibiting Anti-Cancer and Anti-Proliferative Activities
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Described are compounds of Formula I which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-1R), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c-FMS, c-KIT, or PDGFR kinases.
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Paragraph 0422
(2014/09/30)
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- Analogs of isovaleramide, a pharmaceutical composition including the same, and a method of treating central nervous system conditions or diseases
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An isovaleramide analog having at least one of an increased potency, an increased half-life, and an increased stability compared to isovaleramide. The isovaleramide analog is a cyclic analog or a noncyclic analog. The isovaleramide analog is formulated into a pharmaceutical composition. A method of treating a central nervous system condition or disease is also disclosed. The method comprises administering an isovaleramide analog to a patient suffering from the central nervous system condition or disease.
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Page/Page column 9
(2010/02/15)
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