Geldanamycins: Potent Hsp90 Inhibitors with Significant Potential in Cancer Therapy

Sep 21, 2026

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Geldanamycin, an ansa-macrolide derived from Streptomyces hygroscopicus, functions as a potent inhibitor of heat shock protein Hsp90 and shows notable antiproliferative activity. Despite strong therapeutic promise, preclinical findings report pronounced hepatotoxicity in animal models and unfavorable pharmacokinetics. Multiple geldanamycin analogs have advanced through clinical trial stages, yet none has completed evaluation or obtained FDA approval. This review summarizes mechanism, pharmacokinetics, and strategies to reduce toxicity while improving clinical potential.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages20

Reading Time50 min

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Abstract

Keywords

Introduction

Geldanamycin

Heat Shock Proteins

Review Geldanamycins: Potent Hsp90 Inhibitors with Significant Potential in Cancer Therapy Omeima Abdullah 1 and Ziad Omran 2, * Citation: Abdullah, O.; Omran, Z. Geldanamycins: Potent Hsp90 Inhibitors with Significant Potential in Cancer Therapy. Int. J. Mol. Sci. 2024, 25, 11293. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms252011293 Academic Editor: Daniela Fiocco Received: 27 August 2024 Revised: 10 October 2024 Accepted: 17 October 2024 Published: 20 October 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia; [oaabdullah@uqu.edu.sa](oaabdullah@uqu.edu.sa) 2 King Abdullah International Medical Research Center, King Saud Bin Abdelaziz University for Health Sciences, Jeddah 21423, Saudi Arabia * Correspondence: [omranz@kaimrc.edu.sa](omranz@kaimrc.edu.sa); Tel.: +966-546461441 Abstract: Geldanamycin, an ansa-macrolide composed of a rigid benzoquinone ring and an aliphatic ansa-bridge, was isolated from Streptomyces hygroscopicus. Geldanamycin is a potent heat shock protein inhibitor with remarkable antiproliferative activity. However, it shows pronounced hepatotoxicity in animal models and unfavorable pharmacokinetic properties. Four geldanamycin analogs have progressed through various phases of clinical trials, but none have yet completed clinical evaluation or received FDA approval. To enhance the efficacy of these Hsp90 inhibitors, strategies such as prodrug approaches or nanocarrier delivery systems could be employed to minimize systemic and organ toxicity. Furthermore, exploring new drug combinations may help overcome resistance, potentially improving therapeutic outcomes. This review discusses the mechanism of action of geldanamycin, its pharmacokinetic properties, and the various approaches employed to alleviate its toxicity and maximize its clinical efficacy. The main focus is on those derivatives that have progressed to clinical trials or that have shown important in vivo activity in preclinical models. Keywords: geldanamycin; ansamycin; cancer; Hsp90; mutasynthesis; PROTAC 1. Introduction Despite the considerable progress made in human genomics and drug discovery in the twenty-first century, cancer remains a leading cause of death worldwide, accounting for at least 10 million deaths in 2020 [1] . Cancer is linked to the overexpression of proteins or chaperones associated with protein folding [2], including heat shock proteins (Hsps), the first identified chaperones, named for their increased levels when cells are exposed to higher-than-normal temperatures. The 90 kDa Hsp (Hsp90), the most abundant human Hsp, plays a crucial role in cellular proteostasis by controlling the folding, stabilization, activation, and degradation of more than 400 client proteins [3] . Among these client proteins are many that are considered oncogenic, such as hypoxia-inducible factor-1 (HIF- 1), platelet-derived growth factor receptor (PDGFR), the estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2) [4] . Thus, inhibiting Hsp90 represents an attractive strategy for cancer management. One potent Hsp90 inhibitor is geldanamycin (Figure 1), a compound first isolated from culture filtrates of the soil actinomycete Streptomyces hygroscopicus var. geldanus var. nova by C. DeBoer and his colleagues in 1970 [5] . Geldanamycin was initially shown to have moderate activity against protozoa, bacteria, and fungi [5], but it was later found to possess potent anticancer activity against a wide range of human cancers through its inhibition of Hsp90 [6] . However, despite its pr

FAQs

What is geldanamycin and what biological target does it inhibit?

Geldanamycin is an ansa-macrolide isolated from Streptomyces hygroscopicus. It is a potent heat shock protein inhibitor, targeting Hsp90 to suppress its function.

Why has geldanamycin not been used widely in clinical settings?

Although it shows strong antiproliferative activity, it exhibits pronounced hepatotoxicity in animal models and unfavorable pharmacokinetic properties, limiting clinical development.

What strategies are proposed to improve Hsp90 inhibitors based on this review?

To enhance efficacy while reducing systemic and organ toxicity, the review suggests prodrug approaches and nanocarrier delivery systems. It also highlights exploring new drug combinations to help overcome resistance and improve outcomes.

Sep 21, 2026

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