- Rationally Designed Polypharmacology: α-Helix Mimetics as Dual Inhibitors of the Oncoproteins Mcl-1 and HDM2
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Protein–protein interactions (PPIs), many of which are dominated by α-helical recognition domains, play key roles in many essential cellular processes, and the dysregulation of these interactions can cause detrimental effects. For instance, aberrant PPIs involving the Bcl-2 protein family can lead to several diseases including cancer, neurodegenerative diseases, and diabetes. Interactions between Bcl-2 pro-life proteins, such as Mcl-1, and pro-death proteins, such as Bim, regulate the intrinsic pathway of apoptosis. p53, a tumor-suppressor protein, also has a pivotal role in apoptosis and is negatively regulated by its E3 ubiquitin ligase HDM2. Both Mcl-1 and HDM2 are upregulated in numerous cancers, and, interestingly, there is crosstalk between both protein pathways. Recently, synergy has been observed between Mcl-1 and HDM2 inhibitors. Towards the development of new anticancer drugs, we herein describe a polypharmacology approach for the dual inhibition of Mcl-1 and HDM2 by employing three densely functionalized isoxazoles, pyrazoles, and thiazoles as mimetics of key α-helical domains of their partner proteins.
- Conlon, Ivie L.,Drennen, Brandon,Lanning, Maryanna E.,Hughes, Samuel,Rothhaas, Rebecca,Wilder, Paul T.,MacKerell, Alexander D.,Fletcher, Steven
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p. 1691 - 1698
(2020/07/04)
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- DUAL INHIBITORS OF THE BCL-2 AND HDM2 FAMILIES THROUGH CO-MIMICRY OF THE BH3 AND P53-ALPHA-HELICES
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The invention relates to dual HDM2/Bcl-2 inhibitors, providing a synergistic effect to help promote apoptosis in tumorigenic cells.
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Paragraph 00286
(2019/03/12)
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- ALKYNYL ALCOHOLS AND METHODS OF USE
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The invention relates to compounds of formula (I), wherein Q, A1-A8, R4 and R5 are as described herein. Compounds of formula (I) and pharmaceutical compositions thereof are useful in the treatment of diseases and disorders in which undesired or over-activation of NF-kB signaling is observed.
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- THIAZOLE DERIVATIVES AND THEIR USE AS P2Y12 RECEPTOR ANTAGONISTS
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The present invention relates to thiazole derivatives of Formula (I) and their use as P2Y12 receptor antagonists in the treatment and/or prevention of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cere
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Page/Page column 54
(2010/11/05)
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- Synthesis of 2-aryl-oxazolo[4,5-c]quinoline-4(5H)-ones and 2-aryl-thiazolo[4,5-c]quinoline-4(5H)-ones
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(Matrix presented) Novel and highly efficient syntheses of oxazolo[4,5-c]quinoline-4(5H)-ones (1) and thiazolo[4,5-c]quinoline-4(5H)-ones (2) from ethyl 2-chlorooxazole-4-carboxylate (4) and ethyl 2-bromo-5-chlorothiazole-4-carboxylate (13), respectively,
- Hodgetts, Kevin J.,Kershaw, Mark T.
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p. 2911 - 2914
(2007/10/03)
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- Synthesis of 2,5-dihalothiazole-4-carboxylates
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An efficient synthesis of 2,5-dihalothiazole-4-carboxylates has been described. Halogenation of aminothiazole carboxylate with NBS or NCS and subsequent diazotization with isoamyl nitrite and halogenation with CuBr2, CuCl2 or CH2I2 provided the corresponding diahalothiazole derivatives. The four-step process described is amenable to scale-up and requires no chromatographic purification in all the steps.
- Okonya, John F,Al-Obeidi, Fahad
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p. 7051 - 7053
(2007/10/03)
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- Regiocontrolled Synthesis of Substituted Thiazoles
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(Formula Presented) The regiocontrolled synthesis of 2,5-disubstituted and 2,4,5-trisubstituted thiazoles from ethyl 2-bromo-5-chloro-4-thiazolecarboxylate 1 using sequential palladium-catalyzed coupling reactions is described.
- Hodgetts, Kevin J.,Kershaw, Mark T.
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p. 1363 - 1365
(2007/10/03)
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