Diverging Novobiocin Anti-Cancer Activity from Neuroprotective Activity through Modification of the Amide Tail

Ghosh, Suman; Liu, Yang; Garg, Gaurav; Anyika, Mercy; McPherson, Nolan T.; Ma, Jiacheng; Dobrowsky, Rick T.; Blagg, Brian S. J.

doi:10.1021/acsmedchemlett.6b00224

Cited by 21 publications

(16 citation statements)

References 35 publications

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“…Cell Culture and Transfection. The iHEK-P301L cells (32) and luciferaseexpressing PC3-MM2 cells (32) were cultured in DMEM supplemented with 10% FBS and 1% penicillin/streptomycin (Invitrogen). Inducible cells were incubated with 3 μg of tetracycline for 72 h. Forty-eight hours before harvest, transfections were performed with 2.5 μL of Lipofectamine 2000 (Invitrogen) per 1 μg of DNA, which was incubated in serum-free Opti-MEM for 5 min before adding the mixture drop-wise to the cells.…”

Section: Methodsmentioning

confidence: 99%

Hsp90 activator Aha1 drives production of pathological tau aggregates

Shelton

Baker

Zheng

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The microtubule-associated protein tau (MAPT, tau) forms neurotoxic aggregates that promote cognitive deficits in tauopathies, the most common of which is Alzheimer's disease (AD). The 90-kDa heat shock protein (Hsp90) chaperone system affects the accumulation of these toxic tau species, which can be modulated with Hsp90 inhibitors. However, many Hsp90 inhibitors are not blood-brain barrier-permeable, and several present associated toxicities. Here, we find that the cochaperone, activator of Hsp90 ATPase homolog 1 (Aha1), dramatically increased the production of aggregated tau. Treatment with an Aha1 inhibitor, KU-177, dramatically reduced the accumulation of insoluble tau. Aha1 colocalized with tau pathology in human brain tissue, and this association positively correlated with AD progression. Aha1 overexpression in the rTg4510 tau transgenic mouse model promoted insoluble and oligomeric tau accumulation leading to a physiological deficit in cognitive function. Overall, these data demonstrate that Aha1 contributes to tau fibril formation and neurotoxicity through Hsp90. This suggests that therapeutics targeting Aha1 may reduce toxic tau oligomers and slow or prevent neurodegenerative disease progression.

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Section: Methodsmentioning

confidence: 99%

Hsp90 activator Aha1 drives production of pathological tau aggregates

Shelton

Baker

Zheng

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…16–23 SAR studies revealed that the benzamide side chain is critical to manifest anti-proliferative activity and modifications to this moiety produced molecules that exhibited increased anti-proliferative activity against multiple cancer cell lines. 18, 20–24 In addition, it was found that the noviose sugar could be replaced with ionizable amines, which resulted in analogues that showed improved potency and solubility. 21–23, 25 In contrast, studies suggested that the coumarin core serves only as a backbone to orient the benzamide and sugar side chains in the binding pocket.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of alkylamino biphenylamides as Hsp90 C-terminal inhibitors

Garg

Zhao

Blagg

2017

Bioorganic & Medicinal Chemistry

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Hsp90 is a promising therapeutic target for the development of anti-cancer agents due to its integral role in the stability and function of proteins associated with all ten hallmarks of cancer. Novobiocin, a coumarin antibiotic, was the first natural product identified that targeted the Hsp90 C-terminal domain and manifested anti-proliferative activity (SKBr3 IC50 ~ 700 μM). Subsequent structural investigations on novobiocin led to analogues with significantly improved anti-proliferative activity against multiple cancer cell lines. In an effort to develop more efficacious and diverse analogues, it was recently found that the coumarin ring of novobiocin could be replaced with the biphenyl core without compromising activity. Based on these prior studies, a series of alkylamino biphenylamides was designed, synthesized and evaluated for anti-proliferative activity against two breast cancer cell lines. SAR studies demonstrated that the incorporation of an alkylamino side chain onto the biphenyl core improved anti-proliferative activity and resulted in compounds that exhibit sub-micromolar to mid-nanomolar activity through Hsp90 inhibition. Importantly, these studies indicate the presence of a hydrophilic region about the central core that can be exploited for the design of new inhibitors.

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“…Synthesis of KU-32 and KU-596 KU-32 was synthesized as previously described. 27 Briefly, acetic anhydride (0.02 mL, 0.21 mmol) was added to a solution of aniline (0.05 g, 0.13 mmol) in CH 2 Cl 2 (1 mL) at room temperature. After reaction completion as indicated by thinlayer chromatography, the solution was concentrated and purified via column chromatography (SiO 2 , 0-5% MeOH in CH 2 Cl 2 ) to afford the acetylated product as a white amorphous solid (0.05 g, 85% yield).…”

Section: Methodsmentioning

confidence: 99%

“…24,25 On the other hand, the novobiocin analogue KU-174 triggered client degradation and exhibited broad cytotoxicity, without inducing the heat shock response. 26 The ability of C-Hsp90 inhibitors to tune the functional outcomes of the Hsp90 chaperone cycle and exert differential therapeutic outcomes 27 makes them very attractive drug candidates against either different types of cancer or neurologic disorders. However, comprehensive mechanistic understanding of the mode of action of such ligands, as well as further rational SAR studies are hampered by the absence of structural or other experimental data characterizing their interaction with Hsp90.…”

Section: Introductionmentioning

confidence: 99%

Molecular insights into the interaction of Hsp90 with allosteric inhibitors targeting the C-terminal domain

Noor

Davis

et al. 2018

Med. Chem. Commun.

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Unique to targeting the C-terminal domain of Hsp90 (C-Hsp90) is the ability to uncouple the cytotoxic and cytoprotective outcomes of Hsp90 modulation. After the identification of novobiocin as a C-Hsp90 interacting ligand a diverse gamut of novologues emerged, from which KU-32 and KU-596 exhibited strong neuroprotective activity. However, further development of these ligands is hampered by the difficulty to obtain structural information on their complexes with Hsp90. Using saturation transfer difference (STD) NMR spectroscopy, we found that the primary binding epitopes of KU-32 and KU596 map at the ring systems of the ligands and specifically the coumarin and biphenyl structures, respectively. Based on both relative and absolute STD effects, we identified KU-596 sites that can be explored to design novel third-generation novologues. In addition, chemical shift perturbations obtained by methyl-TROSY reveal that novologues bind at the cryptic, C-Hsp90 ATP-binding pocket and produce global, long-range structural rearrangements to dimeric Hsp90.

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Diverging Novobiocin Anti-Cancer Activity from Neuroprotective Activity through Modification of the Amide Tail

Cited by 21 publications

References 35 publications

Hsp90 activator Aha1 drives production of pathological tau aggregates

Hsp90 activator Aha1 drives production of pathological tau aggregates

Design, synthesis and biological evaluation of alkylamino biphenylamides as Hsp90 C-terminal inhibitors

Molecular insights into the interaction of Hsp90 with allosteric inhibitors targeting the C-terminal domain

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