Author: Conradie, Daleen ; van der Westhuyzen, Aletta E ; van Otterlo, Willem A L ; Betancourt, Tania ; Pelly, Stephen C ; Kaschula, Catherine H ; Shuster, Charles B ; Ashraf, Naghmana ; Kornienko, Alexander ; Landfair, Taylor ; Loots, Leigh ; Frolova, Liliya V

To improve their aqueous solubility characteristics, water-solubilizing groups were added to some antiproliferative, rigidin-inspired 7-deazahypoxanthine frameworks after molecular modeling seemed to indicate that structural modifications on the C7 and/or C8 phenyl groups would be beneficial. To this end, two sets of 7-deazahypoxanthines were synthesized by way of a multicomponent reaction approach. It was subsequently determined that their antiproliferative activity against HeLa cells was retained for those derivatives with a glycol ether at the 4'-position of the C8 aryl ring system, while also significantly improving their solubility behavior. The best of these compounds were the equipotent 6-[4-(2-ethoxyethoxy)benzoyl]-2-(pent-4-yn-1-yl)-5-phenyl-1,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 33 and 6-[4-(2-ethoxyethoxy)benzoyl]-5-(3-fluorophenyl)-2-(pent-4-yn-1-yl)-1,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 59. Similarly to the parent 1, the new derivatives were also potent inhibitors of tubulin assembly. In treated HeLa cells, live cell confocal microscopy demonstrated their impact on microtubulin dynamics and spindle morphology, which is the upstream trigger of mitotic delay and cell death.

01 Jan 2021·ImmunologyQ3 · MEDICINE

Inhibition of the NLRP3 inflammasome by HSP90 inhibitors

Q3 · MEDICINE

Article

Author: Arunasalam, Kanisa ; Zarganes‐Tzitzikas, Tryfon ; Di Daniel, Elena ; Davis, John B. ; Cook, James ; Nizami, Sohaib ; Brough, David ; Green, Jack ; Lawrence, Catherine B.

SummaryExcessive and dysregulated inflammation is known to contribute to disease progression. HSP90 is an intracellular chaperone known to regulate inflammatory processes including the NLRP3 inflammasome and secretion of the pro‐inflammatory cytokine interleukin(IL)‐1β. Here, primarily using an in vitro inflammasome ASC speck assay, and an in vivo model of murine peritonitis, we tested the utility of HSP90 inhibitors as anti‐inflammatory molecules. We report that the HSP90 inhibitor EC144 effectively inhibited inflammatory processes including priming and activation of NLRP3 in vitro and in vivo. A specific inhibitor of the β HSP90 isoform was ineffective suggesting the importance of the α isoform in inflammatory signalling. EC144 inhibited IL‐1β and IL‐6 in vivo when administered orally, and was brain‐penetrant. These data suggest that HSP90 inhibitors may be useful for targeting inflammation in diverse diseases that are worsened by the presence of inflammation.

01 May 2009·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Discovery of 5-substituted 2-amino-4-chloro-8-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7,8-dihydropteridin-6(5H)-ones as potent and selective Hsp90 inhibitors

Q4 · MEDICINE

Article

Author: Neela Patel ; Ellyn Shocron ; Connie L. Sun ; Aimin Song ; Xiaoyuan Li

A new series of compounds, 5-substituted 2-amino-4-chloro-8-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7,8-dihydropteridin-6(5H)-ones, have been designed and identified as potent and selective inhibitors of Hsp90. These compounds demonstrated nanomolar potency toward both Hsp90-regulated Her2 degradation and the growth of a panel of human tumor cell lines in cell-based assays. High selectivity of these compounds toward Hsp90 was evident given that they did not inhibit a panel of 34 kinases at 10microM. The structure-activity relationship (SAR) of this series is reported here.

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Indication	Highest Phase	Country/Location	Organization	Date
Stomach Cancer	Preclinical	US	Biogen, Inc.	31 Aug 2012

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