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Givinostat Hydrochloride

Product NameGivinostat Hydrochloride
CAS1019889-35-0
MFC27H37N3O6
MW499.61
EINECS
MOL File1019889-35-0.mol

Usage And Synthesis

Uses

Onalespib lactate is a potent and cross the blood-brain barrier heat-shock-protein-90 (Hsp90) inhibitor with an Kd value of 0.71 nM. Onalespib lactate inhibits the proliferation, survival and migration. Onalespib lactate decreases the expression of EGFR, p-EGFR, AKT, P-AKT, ERK1/2, P-ERK1/2, S6, P-S6 protein. Onalespib lactate shows antitumor activity. Onalespib lactate has the potential for the research of non-small cell lung cancer (NSCLC)[1][2][3][4].

in vivo

Onalespib lactate (30 mg/kg; i.v.; once) crosses the blood-brain barrier (BBB) and causes sustained inhibition of HSP90 in 6-week-old ICR mice^[2].
Onalespib lactate (0.5 μM; from 5 to 10 days post-transplant) and TMZ (10 μM) reduce tumor growth and extend survival in zebrafish embryos^[2].
Onalespib lactate (5, 10 mg/kg for HCT116 xenografts, 20 mg/kg for A431 xenografts; i.p.; daily for 3 days) shows anti-tumor activity in HCT116 and A431 xenografts^[3].

Animal Model:	Female nu/nu Balb/c mice (HCT116 and A431 xenografts)^[3]
Dosage:	5, 10 mg/kg for HCT116 xenografts, 20 mg/kg for A431 xenografts
Administration:	I.p.; on day 1, 2, and 3 days
Result:	Inhibited tumor growth and had a median survival of 9.5 days and the maximum survival was 14 days in HCT116 xenografts, reduced the tumor size significantly by 32% in A431 xenografts.

IC 50

HSP90: 0.71 nM (Kd)

References

[1] Riess JW, et al. Erlotinib and Onalespib Lactate Focused on EGFR Exon 20 Insertion Non-Small Cell Lung Cancer (NSCLC): A California Cancer Consortium Phase I/II Trial (NCI 9878). Clin Lung Cancer. 2021 Nov;22(6):541-548. DOI:10.1016/j.cllc.2021.05.001
[2] Canella A, et al. Efficacy of Onalespib, a Long-Acting Second-Generation HSP90 Inhibitor, as a Single Agent and in Combination with Temozolomide against Malignant Gliomas. Clin Cancer Res. 2017 Oct 15;23(20):6215-6226. DOI:10.1158/1078-0432.CCR-16-3151
[3] Spiegelberg D, et al. The HSP90 inhibitor Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy: an in vitro and in vivo approach. Sci Rep. 2020 Apr 3;10(1):5923. DOI:10.1038/s41598-020-62293-4
[4] Woodhead AJ, et al. Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design. J Med Chem. 2010 Aug 26;53(16):5956-69. DOI:10.1021/jm100060b

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