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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 prominent C-terminal inhibitors are coumarin derived compounds (novobiocin, chlorobiocin, coumermycin (Figure 3.12) [150]. Curcumin, epigallocatechin–3-gallate (EGCG), cisplatin, and silybin are the C-terminal Hsp90 inhibitors without the coumarin nucleus (Figure 3.13) [151]. Novobiocin is obtained from Streptomyces niveus and is used for the treatment of various bacterial infections. It is a DNA gyrase inhibitor, which blocks the ATPase activity of the enzyme. This coumarin antibiotic was the first carboxyl terminus Hsp90 inhibitor discovered [152]. The novobiocin binding site was revealed to be adjacent to the C-terminal dimerization domain (amino acid sequence 538–728). This site was also found to have an affinity for ATP nucleotide. Hence, it was concluded that novobiocin is a competitive inhibitor of ATP nucleotide at Hsp90’s C-domain [150, 153, 154]. Further experimentation proved that novobiocin do not bind to N-terminal ATP binding cleft. However, it was practically shown that binding of novobiocin to the C-domain’s ATP binding region leads to displacement of inhibitors (ATP, molecules) from the N-terminal ATP binding cleft (Bergerat’s fold). This may be attributed to chaperone’s flexible nature which leads to crosstalk between N and C domains of the protein. Additionally, it was also demonstrated that novobiocin binding prevents association of co-chaperones (p23, Raf1, mutant p53 and Hsc70) with Hsp90 [152]. Further, numerous derivatives of novobiocin were synthesized and evaluated for their Hsp90 inhibitory potential. These analogs were found to be 100–1000 times more potent than novobiocin in terms of Hsp90 inhibition. Additionally, structure-activity relationship studies were also carried out with these synthesized novobiocin analogs [150]. The conclusions of the SAR studies were used to design more potent and selective (will not bind to DNA gyrase) Hsp90 C-terminal inhibitors. This led to the identification of two selective and potent natural product inhibitors of Hsp90 chaperone (DHN1 and DHN2, Figure 3.12) [151, 155]. Chlorobiocin and coumarimycin were reported to act in a similar fashion as that of novobiocin [151, 152].
Repurposing of Streptomyces antibiotics as adenosine deaminase inhibitors by pharmacophore modeling, docking, molecular dynamics, and in vitro studies
Published in Journal of Receptors and Signal Transduction, 2020
K. G. Arun, C. S. Sharanya, J. Abhithaj, C. Sadasivan
Novobiocin was marketed as Albamycin against bacterial infections in 1960s, and later, it was withdrawn from markets due to the lack of efficiency. However, novobiocin was considered as a safer drug, and hence, it can be used as a good lead compound for developing drugs against other diseases. The study showed that this aminocoumarin antibiotic from Streptomyces niveus can be repositioned as a potential candidate for developing ADA inhibitor drug.