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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Unfortunately, although geldanamycin was active in preclinical studies, it was a poor candidate for clinical trials due to its poor water solubility, instability, and in vivo toxicity in animal models. Therefore, during the 1980s, the National Cancer Institute (NCI) worked on several geldanamycin analogs to develop more water-soluble and less-toxic versions of the drug. Eventually, in 1992, 17-allylamino-demethoxygeldanamycin (tanespimycin, 17-AAG) (Figure 6.110) was produced in collaboration with the company Kosan. This analogue was shown to bind specifically to HSP90 in a similar manner to geldanamycin but with a lower affinity. Therefore, it is surprising that tanespimycin and geldanamycin have similar cytotoxicities toward tumor cells in vitro. However, tanespimycin had a better toxicity profile than geldanamycin and was a preferred clinical candidate, reaching Phase I/II clinical trials with Bristol-Myers Squibb (BMS). Preliminary results indicated that a target dose of tanespimycin could be achieved without dose-limiting toxicity, and it was notably less hepatotoxic than geldanamycin and could be administered at higher doses. The most common side effects were anorexia, nausea, and diarrhea, all of which could be dose limiting. Less-common side effects included hepatotoxicity, fatigue and blood dyscrasias (e.g., thrombocytopenia, anemia). Despite being in late-stage clinical trials for the treatment of multiple myeloma, in 2010 BMS halted development of tanespimycin without explanation, although some observers suggested that the relatively short patent life and cost of manufacture may have played a role.
Novel Anti-Cancer Drugs Based On Hsp90 Inhibitory Mechanisms: A Recent Report
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
The quest for the rapid discovery of novel Hsp90 inhibitor scaffold resulted in the screening of compounds by high throughput screening (HTS). In one such approach, first 2000 ATP binding proteins were adsorbed on an ATP-affinity column by loading cell lysates. Thereafter, mass spectrometry was used to identify compounds that selectively displace Hsp90 in the column. These studies identified benzamide derivatives as a new Hsp90 inhibitor chemotypes. SNX 2122 (Figure 3.10) was found to be suitable for clinical evaluation. However, this compound has variable bioavailability and produces polymorphic crystals and therefore was found unsuitable for further development [116]. Hence, a glycine prodrug of SNX 2122 (PF–04929113, SNX 5422, Figure 3.10) was developed and this molecule entered clinical trial as an oral inhibitor of Hsp90 in May 2007 [117, 118]. Additionally, the above HTS approach also generated several lead molecules, which were optimized by SAR and X-ray crystallographic studies. These research works lead to the identification of two clinically evaluable drug molecules (Figure 3.10). TAS–116 and XL–888 showed a better safety profile (like minimum ocular toxicity for TAS–116) in preclinical models [119]. Hence, these two molecules are currently in Phase I/II of clinical trials [120]. From the aforestated discussion on Hsp90 inhibitors, it is evident that 18 molecules reached various phases of clinical trials. Currently, six of them are undergoing Phase-I/II/III study either alone or in combination with other antineoplastic agents (Table 3.2) [120, 121]. The structure of one of the agents (DS–2248) is not disclosed by Daichi Sankyo Company Limited, Japan. Out of 18 molecules, only tanespimycin, retaspimycin and STA 9090 reached phase III of clinical trials [116, 121, 122].
Berberine regulates the Notch1/PTEN/PI3K/AKT/mTOR pathway and acts synergistically with 17-AAG and SAHA in SW480 colon cancer cells
Published in Pharmaceutical Biology, 2021
Ge Li, Chuang Zhang, Wei Liang, Yanbing Zhang, Yunheng Shen, Xinhui Tian
The human colon cancer cells SW480, the human hepatoma cancer cells HuH7, QGY7701 and QGY7703, the human breast cancer cells MCF-7, the human lung cancer cells A549 and the human acute monocytic leukaemia cells THP-1 were obtained from the Cell Resource Centre, Institute of Life Sciences, Chinese Academy of Medical Science. Berberine (>98% pure) was purchased from Sigma-Aldrich (St. Louis, MO). Tanespimycin (17-AAG) and Vorinostat (SAHA) were from Medchem Express (Monmouth Junction, NJ). L-15 medium, DMEM medium and penicillin/streptomycin were from Gibco (Carlsbad, CA). Foetal bovine serum was from Biological Industries (Cromwell, CT). Hoechst 33342 dye was from Sigma-Aldrich Corp. (St. Louis, MO). Annexin V-FITC was from BD Biosciences (San Jose, CA). Cell Cycle and Apoptosis Analysis Kit was from Beyotime (Nantong, China). Protease inhibitor cocktail and BCA protein quantitation kit were from Thermo Fisher (Rockford, IL).
Heat shock proteins as a new, promising target of multiple myeloma therapy
Published in Expert Review of Hematology, 2020
Sebastian Grosicki, Martyna Bednarczyk, Grażyna Janikowska
The first HSP90 inhibitor that has entered clinical trials is tanespimycin and is therefore best studied. It is the first HSP inhibitor in its class [49–51]. The combination of tanespimycin and bortezomib showed significant and sustained efficacy response with acceptable toxicity in the phase I/II study in patients with relapsed and relapsed/refractory multiple myeloma (R/R MM). Additional studies of subsequent phases will allow to additionally assess the optimal dosage of other drugs and schedules, as well as confirm the effectiveness and tolerability of such treatment [52].
Novel avenues for identification of new antifungal drugs and current challenges
Published in Expert Opinion on Drug Discovery, 2022
Savarirajan et al. [63] focused on finding new antifungals in nature. They discovered that extracts from Asparagus racemosus cladodes and seeds of Cassia occidentalis have strong antifungal activity against dermatophytic fungal species, Trichophyton mentagrophytes, Trichophyton terrestre, Microsporum gypseum, and Microsporum nanum. They analyzed the extracts and partially characterized the antifungal compounds. Two compounds from C. occidentalis were described as hydroxy anthraquinones, while the active ingredient from the A. racemosus extract was a saponin. The antidermatophytic activity of the plant anthraquinones and the saponin is associated with insignificant hemolytic activity, which makes these compounds ideal for antifungal therapy. Heat shock protein 90 (Hsp90) has been shown to develop and maintain resistance to antimycotics in fungi. Thus, the use of Hsp90 as a new target provides a much needed strategy to improve the treatment of fungal diseases, as this increases the efficacy of existing antifungals and blocks the development of drug resistance. Geldanamycin, a 1,4-benzoquinone ansamycin antitumor antibiotic discovered in Streptomyces hygroscopicus [64], has been identified as one of the potential inhibitors of Hsp90 in fungal diseases. However, its anticancer activity disqualified it, so its derivatives, tanespimycin (17-N-allylamino-17-demethoxygeldanamycin, 17-AAG) and 17-N,N-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), were proposed as inhibitors of Hsp90 in fungi and dramatically increased the efficacy of fluconazole against C. albicans [65]. The search for selective Hsp90 inhibitors in fungi continues, and new compounds, e.g. SNX-2112 and CMLD-013075 with significant, up to >25-fold binding selectivity for fungal Hsp90 compared to the inhibition of Hsp90 in human cells, have recently been described [66], see Figure 1.