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Review
. 2024 Oct 20;25(20):11293.
doi: 10.3390/ijms252011293.

Geldanamycins: Potent Hsp90 Inhibitors with Significant Potential in Cancer Therapy

Omeima Abdullah  1 , Ziad Omran  2
Affiliations
Review

Geldanamycins: Potent Hsp90 Inhibitors with Significant Potential in Cancer Therapy

Omeima Abdullah et al. Int J Mol Sci. .

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: Hsp90; PROTAC; ansamycin; cancer; geldanamycin; mutasynthesis.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Chemical structure of geldanamycin [5].
Figure 2
Figure 2
Binding interactions of geldanamycin with Hsp90. The structure was generated from PDB: 1YET [31].
Figure 3
Figure 3
Inhibition of Hsp90 by geldanamycin and subsequent degradation of its client proteins [41].
Figure 4
Figure 4
Two-electron reduction of geldanamycin by NQO1 [44].
Figure 5
Figure 5
Biosynthesis of geldanamycin [51,52].
Figure 6
Figure 6
1,4-Michael reaction cascade between geldanamycin and GSH [54].
Figure 7
Figure 7
One-electron reduction of geldanamycin [44].
Figure 8
Figure 8
Addition of N-acetylcysteine methyl ester to geldanamycin and its derivatives substituted at position 19 [59,60,61].
Figure 9
Figure 9
Trans–cis-lactam isomerization in geldanamycin [45].
Figure 10
Figure 10
Semi-synthesis of 17-AAG and 17-DMAG [62,63].
Figure 11
Figure 11
Chemical structure of gamitrinib, a mitochondria-targeted HSP90 inhibitor [70].
Figure 12
Figure 12
Chemical synthesis of retaspimycin hydrochloride and its locked benzoxazole analog 3 [72].
Figure 13
Figure 13
Chemical synthesis of geldanamycin carbamate derivative 4 [72].
Figure 14
Figure 14
Chemical synthesis of geldanamycin benzoxazole derivative 5 [74].
Figure 15
Figure 15
Chemical synthesis of 17-propargylamine-17-demethoxygeldanamycin 6 [75].
Figure 16
Figure 16
Synthesis of the triazole derivative 7 [76].
Figure 17
Figure 17
Quaternization of the quinuclidine analog of geldanamycin 8 [43].
Figure 18
Figure 18
Chemical structure of KOSN1559 prepared by engineered biosynthesis [77].
Figure 19
Figure 19
Mutasynthetic preparation of geldanamycin derivatives 17–23 [52].
Figure 20
Figure 20
Chemical structures of estradiol–geldanamycin (24) and testosterone–geldanamycin (25) hybrids [90,91].
Figure 21
Figure 21
Carbohydrates-based prodrugs of geldanamycin [93].
Figure 22
Figure 22
Chemical synthesis of the fatty prodrug 29 [100].
Figure 23
Figure 23
Conversion of prodrug 30 into macbecin II and then into macbecin I at physiological pH [101].
Figure 24
Figure 24
Chemical synthesis of geldanamycin-based PROTAC 31 [102].
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