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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In the late 1960s, the Upjohn Company discovered geldanamycin (Figure 6.110), a natural product isolated from Streptomyces hygroscopicus, that has a suitable shape to interact in a “pocket” of the N-terminal domain of HSP90, thus blocking its ability to assist in the folding of proteins. Geldanamycin is a benzoquinone ansamycin, a member of a family of natural products originally attributed with weak antibiotic activity but later discovered to have potent antitumor activity. A natural product with similar activity, radicicol, was isolated from the mycoparasite Humicola fuscoatra (Figure 6.110).Structures of geldanamycin, 17-AAG (Tanespimycin), 17-DMAG, and radicicol.
Chikungunya Virus Infection
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
D. Velmurugan, K. Manish, D. Gayathri
Rathore et al. (2014) determined the role of heat shock protein-90 (HSP-90) during CHIKV infection. The HSP-90 inhibitor geldanamycin was found to bind in the ATP binding site on HSP-90, rendering this protein in an open conformation. Geldanamycin treatment reduced CHIKV infection by nearly 2.5 log suggesting a significant involvement of HSP-90 during the CHIKV infection cycle. Their experiments with HSP-90 inhibitors on CHIKV replication suggest that blocking the chaperone function of HSP-90 did not affect its protein level or its transcription but resulted in a marked, early reduction in the levels of both viral RNA and protein.
Overview of Molecular Pathways in Melanoma
Published in Sanjiv S. Agarwala, Vernon K. Sondak, Melanoma, 2008
Inhibition of Hsp90 via 17-allylamino-17-demethoxygeldanamycin (17-AAG) or 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) occurs through degradation of Hsp90-chaperoned proteins. Chaperoned proteins include but are not limited to RAF, Akt, VEGF, HIF-1, CDK4, survivin, hTERT, Met, and MMP2 (53). Hsp90 inhibition is interesting for melanoma, not only for the potential impact on multiple pathways but also for the possible selectivity for V600E BRAF. Serial tumor biopsies of melanoma patients pre- and posttreatment with 17-AAG showed downregulation of the MAPK pathway as evidenced by decreased phospho-ERK expression that was not accompanied by decreased wild-type BRAF expression (54), corroborating preclinical findings (55). Several phase I trials of 17-AAG in combination with other therapies are open, and a phase II trial of single agent 17-AAG recently completed accrual.
Mitochondria targeting molecular transporters: synthesis, lipophilic effect, and ionic complex
Published in Drug Delivery, 2022
Akula S. N. Murthy, Sanket Das, Tejinder Singh, Tae-Wan Kim, Nasim Sepay, Seob Jeon, Jungkyun Im
Next, we tested the mitochondria drug targeting capability of the molecular transporter. Since the fluorescent probe was no longer necessary and needed to be replaced by a drug, G4-Nal without FITC was used. First, in vitro stability of G4-Nal in PBS and human plasma was studied. As shown in Figure S7, the percentage of intact G4-Nal was 93.6% in PBS and 81.3% in human plasma, demonstrating sufficient stability to reach mitochondria. Geldanamycin (GA) was used as a model cargo drug. GA is a well-known antitumor antibiotic that inhibits the function of heat shock protein 90 (Hsp90), which is a potential target for cancer therapy (Franke et al., 2013). Since it belongs to a family of molecular chaperones, Hsp90 helps stabilize numerous proteins inside cells to protect protein folding, preventing the apoptosis process. Moreover, mitochondrial Hsp90s are involved in cancer signaling networks that promote tumor development and metastasis (Kang et al., 2009). Since Hsp90s are overexpressed in cancerous cells, inhibition of Hsp90 in mitochondria can prevent disease progression and block the antiapoptotic nature of Hsp90.
Investigation of anticancer activities of STA-9090 (ganetespib) as a second generation HSP90 inhibitor in Saos-2 osteosarcoma cells
Published in Journal of Chemotherapy, 2021
STA-9090 (also known as ganetespib) is a potent second generation small-molecule inhibitor of HSP90. Being structurally unrelated to geldanamycin and its analogs; STA-9090 selectively binds to HSP90 NTD domain and inhibits ATPase function of HSP90 (Figure 1). STA-9090 has anticancer activities in a wide variety of hematological and solid tumour cell lines. Compared with geldanamycin and its derivatives, STA-9090 exhibits more anti-proliferative feature including less hepatotoxicity and favourable safety profile in different cancer subtypes. In pre-clinical study, STA-9090 significantly disrupted oncogenic cellular processes resulted in inhibition of receptor tyrosine kinases signalling pathways and differential regulation of Cyclins/CDKs, and modulation of apoptotic and cell cycle arrest processes in cancer cells.12,17,18 Clinical phase studies evaluating STA-9090 as a front-line chemotherapeutic for a range of cancer patients including lung, pancreas, squamous, leukaemia, ovarian, breast, cervical and esophagus have been proceeded (www.clinicaltrials.gov).
Spectrum of candidate molecules against Chikungunya virus - an insight into the antiviral screening platforms
Published in Expert Review of Anti-infective Therapy, 2019
Shree Madhu Bhat, Piya Paul Mudgal, Sudheesh n, Govindakarnavar Arunkumar
Drug discovery mainly focuses on viruses, as their proteins offer direct targets of inhibition. However, the fact that viruses depend on the host cells for survival may be harnessed, towards directing our efforts in pursuing host and its factors as potential targets to induce the antiviral effect. By targeting the host cell, resistance issues cropping up with most of the virus targeted antivirals may be better tackled [33]. Additionally, host cell targeting antivirals may confer coverage for a wider range of viral genotypes/serotypes. Furin cleaves surface glycoproteins E2/E3 and regulates the release of mature virions. Decanoyl-RVKR-chloromethyl ketone targets furin and inhibits its activity [78].HSP-90 interacts with nsP3 and nsP4 during replication and helps in folding and assembly of virions. Geldanamycin is the inhibitor for HSP-90 [79].Protein disulfide isomerase adds disulfide bonds required for folding and stabilization of virions. Auranofin and EN460 are two compounds that can inhibit its activity [80].