Following the design path of isoform-selective Hsp90 inhibitors : small differences, great opportunities

Dernovšek, Jaka (avtor), Tomašič, Tihomir (avtor)

The heat shock protein 90 (Hsp90) family consists of four highly conserved isoforms: the mitochondrial TRAP-1, the endoplasmic reticulum-localised Grp94, and the cytoplasmic Hsp90α and Hsp90β. Since the late 1990s, this family has been extensively studied as a potential target for the treatment of cancer, neurological disorders, and infectious diseases. The initial approach was to develop non-selective, so-called pan-Hsp90 ATP-competitive inhibitors of the N-terminal domain. Many of these agents were tested in clinical trials, mainly for the treatment of cancer, but none of them succeeded in the clinic. This was mainly due to the lack of efficacy and various toxicities associated with the induction of heat shock response (HSR). This lack of success has prompted a turn to new approaches of Hsp90 inhibition. Thus, inhibitors selective for a particular isoform of Hsp90 have been developed. These isoform-selective inhibitors do not induce HSR and have a more targeted effect because not all client proteins are equally dependent on all four paralogues of Hsp90. However, it is extremely difficult to develop such selective compounds because the family is highly conserved. Hsp90α and Hsp90β have an amazing 95% identity of the N-terminal ATP binding site, differing only in two amino acid residues. Therefore, the focus of this review is to fully elucidate the key structural features of the selective inhibitor classes in terms of binding site dissimilarities. In addition to a methodological characterisation of the structure-activity relationships, the main advantages of selective inhibition of the TRAP-1, Grp94, Hsp90α and Hsp90β isoforms are discussed.

• Jezik: Angleški jezik
• Ključne besede: cancer, drug design, Hsp90, inhibitor, selectivity
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2023
• Št. strani: 20 str.
• Številčenje: Vol. 245, art. 108396
• PID: 20.500.12556/RUL-148678
• UDK: 615.4:54
• ISSN pri članku: 0163-7258
• DOI: 10.1016/j.pharmthera.2023.108396
• COBISS.SI-ID: 147241219
• Datum objave v RUL: 29.08.2023

Gradivo je del revije

• Naslov: Pharmacology & therapeutics
• Skrajšan naslov: Pharmacol. ther.
• Založnik: Elsevier
• ISSN: 0163-7258
• COBISS.SI-ID: 26118144

Licence

• Licenca: CC BY-NC-ND 4.0, Creative Commons Priznanje avtorstva-Nekomercialno-Brez predelav 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by-nc-nd/4.0/deed.sl
• Opis: Najbolj omejujoča licenca Creative Commons. Uporabniki lahko prenesejo in delijo delo v nekomercialne namene in ga ne smejo uporabiti za nobene druge namene.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: zasnova zdravila, selektivnost, inhibitorji, Hsp90, rak, medicina, farmacevtska kemija

Projekti

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Številka projekta: P1-0208
• Naslov: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Številka projekta: J1-1717
• Naslov: Razvoj novih zaviralcev Hsp90 s protitumornim delovanjem