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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.
Tyrosine Kinase Inhibitors: Targets Other Than FLT3, BCR-ABL, and c-KIT
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Suzanne R. Hayman, Judith E. Karp
Radicicol is a macrocyclic antifungal antibiotic, which is chemically distinct from the BA antibiotic family, but nonetheless targets the ATP/ADP-binding site in the amino terminus of Hsp90, with resultant inhibition of ATPase activity and degradation of Hsp90 client proteins (31). While radicicol has a 50-fold greater binding affinity than GA, by itself it has almost no therapeutic activity in animals because of its instability, perhaps due to epoxy and unsaturated carbonyl groups in its chemical structure (32). However, radicicol oxime derivatives, particularly KF25706 and KF58333, have shown potent antitumor activity in vivo against several human tumor xenograft models, including breast, colon, and epidermoid carcinoma when administered intravenously (31). In addition, KF58333 was found to inhibit VEGF secretion, which was accompanied by a decrease in VEGF mRNA expression in breast cancer cell lines and a decrease in angiogenesis in nude mouse xenografts (31).
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
Radicicol (RD) is the other 1st generation, natural product N-terminal Hsp90 inhibitors, which exhibited significant in vitro anticancer activity. It is a macrocyclic lactone antibiotic which was first isolated from the fungus Microsporium bonorden in 1953 [79]. The binding orientation of radicicol at Hsp90’s ATP binding cleft was found to be different from that of geldanamycin [59, 80]. It is a more potent inhibitor of the chaperone than geldanamycin (Kd of radicicol in ATPase assay = 19 nM; Kd of geldanamycin = 1.2 µM). Unfortunately, it was found to be inactive in vivo because of chemical instability (presence of labile allylic epoxide and α, β, γ, δ-unsaturated ketone). Therefore, it was not found to be a viable candidate for further clinical development. Hence, various derivatives of radicicol with less chemical instability were (Figure 3.6) synthesized and evaluated for their Hsp90 suppression potential [81–83]. A few of them were found to be less potent than radicicol in terms of attenuating Hsp90 ATPase function. The radicicoloximes exhibited comparable potency to that of radicicol [81]. Furthermore, they were found to be effective in the in vitro models wherein they reduced tumor size in a 30-day period [81, 84]. However, the stereochemical complexities associated with these oxime derivatives (mixture of E and Z isomers) restricted their further development [85]. The complexity of radicicol molecule in general also effected research on future development of this scaffold [85]. Luckily, the anticancer studies from RD and their derivatives identified a simple scaffold (resorcinol/4-chloro resorcinol) for the future discovery of Hsp90 inhibitors.
Qiangjing tablets ameliorate asthenozoospermia via mitochondrial ubiquitination and mitophagy mediated by LKB1/AMPK/ULK1 signaling
Published in Pharmaceutical Biology, 2023
Guangsen Li, Yuanjie Xu, Yingxi Li, Degui Chang, Peihai Zhang, Ziyang Ma, Di’ang Chen, Yaodong You, Xiaopeng Huang, Jian Cai
As indicated in Figure 5, the ameliorative effect of the QJT treatment on the pathological manifestations in ORN-treated rats was obviously neutralized by radicicol treatment (Figure 5(A)). Radicicol treatment was expected to significantly reduce the QJT-enhanced relative protein expressions levels of LKB1, AMPKα, and ULK1, while only decreasing the p-AMPKα and ULK1 levels, with no statistical difference in ORN-treated rats (Figure 5(B–F)). Furthermore, the improvement in mitochondrial morphology by QJT treatment was also significantly offset by radicicol treatment in ORN-treated rats (Figure 5(G)). The increased levels of Beclin-1, LC3-II, SCF, and Parkin, and the reduced expression of p62 caused by QJT treatment were also reversed by radicicol treatment in ORN-treated rats (Figure 5(H–P)). Thus, QJT enhanced mitophagy and mitochondrial ubiquitination via the LKB1/AMPK/ULK1 signaling pathway in ORN-treated rats.
Discovery of small molecule inhibitors of Leishmania braziliensis Hsp90 chaperone
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Fernanda A. H. Batista, Sérgio L. Ramos, Giusy Tassone, Andrei Leitão, Carlos A. Montanari, Maurizio Botta, Mattia Mori, Júlio C. Borges
The interaction of Hsp90 proteins with different compounds was monitored through the melting temperature (Tm) of each protein in the presence of a fixed concentration of the target compound by differential scanning fluorimetry (DSF) also referred as thermal shift assay33. A final concentration of 10 µM of dimeric LbHsp90 and 20 µM of monomeric LbHsp90N in 40 mM Hepes buffer (pH 7.5) containing 100 mM KCl were used. The DMSO concentration in each sample was fixed at 2.5% (v/v). Prior to the readings, the samples were incubated for 30 min on ice. The fluorophore Sypro Orange (Life Technologies) was used as fluorescent probe. The experiments were performed at a thermocycler CFX96 Touch Real Time PCR Detection System (BioRad) and the data were analysed using the CFX Manager software (BioRad). As positive controls, 100 µM of GA and Radicicol (RDC) were used.
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
Several small molecule inhibitors of HSP90 function have been introduced into clinical trials. The best known are derivatives of antibiotics: benzoquinone ansamycin GA or macrolide radicicol [47]. These molecules are not structurally bound (Figure 2), but each one them binds to a nucleotide binding site in the N-terminal domain with much greater affinity than ATP or ADP. It leads to increased degradation of client proteins through the proteasome pathway [48] GA, analogues GA and radicicol were before and now are important tools in discovering unrecognized interactions of HSP90 and client proteins in normal and cancer cells.