Onalespib | CAS# 912999-49-6 | HSP90 inhibitor

MedKoo Cat#: 200317 | Name: Onalespib free base

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Onalespib, also known as AT13387 , is a synthetic, orally bioavailable, small-molecule inhibitor of heat shock protein 90 (Hsp90) with potential antineoplastic activity. Hsp90 inhibitor AT13387 selectively binds to Hsp90, thereby inhibiting its chaperone function and promoting the degradation of oncogenic signaling proteins involved in tumor cell proliferation and survival. Hsp90, a chaperone protein upregulated in a variety of tumor cells, regulates the folding, stability and degradation of many oncogenic signaling proteins.

Chemical Structure

Onalespib free base

CAS#912999-49-6 (free base)

Theoretical Analysis

MedKoo Cat#: 200317

Name: Onalespib free base

CAS#: 912999-49-6 (free base)

Chemical Formula: C24H31N3O3

Exact Mass: 409.2365

Molecular Weight: 409.52

Elemental Analysis: C, 70.39; H, 7.63; N, 10.26; O, 11.7

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 400.00	Ready to ship
100mg	USD 700.00	Ready to ship
200mg	USD 1,050.00	Ready to ship
500mg	USD 1,850.00	Ready to ship
1g	USD 2,850.00	Ready to ship
2g	USD 4,650.00	Ready to ship

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Related CAS #

912999-49-6 (free base) 1019889-35-0 (lactate)

Synonym

AT13387; AT-13387; AT 13387; Onalespib; Onalespib lactate.

IUPAC/Chemical Name

(2,4-dihydroxy-5-isopropylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone

InChi Key

IFRGXKKQHBVPCQ-UHFFFAOYSA-N

InChi Code

InChI=1S/C24H31N3O3/c1-16(2)20-11-21(23(29)12-22(20)28)24(30)27-14-18-5-4-17(10-19(18)15-27)13-26-8-6-25(3)7-9-26/h4-5,10-12,16,28-29H,6-9,13-15H2,1-3H3

SMILES Code

O=C(C1=CC(C(C)C)=C(O)C=C1O)N2CC3=C(C=C(CN4CCN(C)CC4)C=C3)C2

Appearance

White solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Related CAS# CAS#912999-49-6 (AT13387 free base), CAS#1019889-35-0 (AT13387 lactate)

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#C21R10B23

View CoA: current batch, lot#PG20629

QC Data

View QC data: current batch, lot#PG20629.

View QC data: current batch, Lot#C21R10B23

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Onalespib (AT13387) is a long-acting second-generation Hsp90 inhibitor with a Kd of 0.71 nM

In vitro activity:

The effect of AT13387 on in vitro radio-sensitization was assessed using a clonogenic assay. The amplitude of the effects of 100 nM AT13387 on the global proteome was significantly lower than that of 3 μM AT13387. Interestingly, except for Hsp70, the abundance of any other protein did not reach beyond the 1.5-fold abundance (log scale) level. The magnitude observed on protein levels (total 2145 significantly affected protein out of 5086) suggests that the 3 μM AT13387 concentration would not be selective. Therefore, when given at a dose producing such drug levels in patients, it seems unlikely that the cumulative effect of the drug would be selective for cancer treatment. Altogether, the data suggest that a sub-toxic concentration of AT13387 can cause radio-sensitization regardless of the specific oncogenic driver(s) present in the cell lines. Clin Cancer Res. 2020 Oct 1; 26(19): 5246–5257. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541797/

In vivo activity:

Following the determination of the pharmacokinetic profile of AT13387, it was sought to determine the duration for which AT13387 can exert its effects in vivo. To investigate these effects, a single 40 mg/kg dose of AT13387 was administered at 0 hours, and a second 40 mg/kg dose at 96 hours, to mice bearing UMSCC74B xenografts. The expression of Hsp70 was analyzed in the tumor at the various time points as previously described. Following administration, pharmacodynamics studies showed that the expression of chaperone protein Hsp70, our biomarker for Hsp90 activity, was upregulated after AT13387 treatment (Figure 5B). This result was confirmed by densitometry analysis, which showed an 8-fold upregulation of Hsp70 expression at 24 and 120 hours (Figure 5B). Nearly 2 to 5-fold increased Hsp70 expression was demonstrated using immunohistochemistry (Figure 5C). This upregulation suggests that AT13387 treatment showed the desired inhibitory effect of Hsp90 inhibition in vivo.This indicates a potential role of the immune component in radiosensitization by AT13387. Clin Cancer Res. 2020 Oct 1; 26(19): 5246–5257. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541797/

	Solvent	mg/mL	mM
Solubility
	DMSO	20.0	48.80

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 409.52 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Lundsten S, Spiegelberg D, Stenerlöw B, Nestor M. The HSP90 inhibitor onalespib potentiates 177Lu‑DOTATATE therapy in neuroendocrine tumor cells. Int J Oncol. 2019 Dec;55(6):1287-1295. doi: 10.3892/ijo.2019.4888. Epub 2019 Sep 30. PMID: 31638190; PMCID: PMC6831206. 2. Mehta RK, Pal S, Kondapi K, Sitto M, Dewar C, Devasia T, Schipper MJ, Thomas DG, Basrur V, Pai MP, Morishima Y, Osawa Y, Pratt WB, Lawrence TS, Nyati MK. Low-Dose Hsp90 Inhibitor Selectively Radiosensitizes HNSCC and Pancreatic Xenografts. Clin Cancer Res. 2020 Oct 1;26(19):5246-5257. doi: 10.1158/1078-0432.CCR-19-3102. Epub 2020 Jul 27. PMID: 32718999; PMCID: PMC7541797. 3. Lundsten S, Spiegelberg D, Raval NR, Nestor M. The radiosensitizer Onalespib increases complete remission in 177LuDOTATATE-treated mice bearing neuroendocrine tumor xenografts. Eur J Nucl Med Mol Imaging. 2020 Apr;47(4):980-990. doi: 10.1007/s00259-019-04673-1. Epub 2020 Jan 7. PMID: 31912256; PMCID: PMC7075859. 4. Mehta RK, Pal S, Kondapi K, Sitto M, Dewar C, Devasia T, Schipper MJ, Thomas DG, Basrur V, Pai MP, Morishima Y, Osawa Y, Pratt WB, Lawrence TS, Nyati MK. Low-Dose Hsp90 Inhibitor Selectively Radiosensitizes HNSCC and Pancreatic Xenografts. Clin Cancer Res. 2020 Oct 1;26(19):5246-5257. doi: 10.1158/1078-0432.CCR-19-3102. Epub 2020 Jul 27. PMID: 32718999; PMCID: PMC7541797.

In vitro protocol:

In vivo protocol:

1. Lundsten S, Spiegelberg D, Raval NR, Nestor M. The radiosensitizer Onalespib increases complete remission in 177LuDOTATATE-treated mice bearing neuroendocrine tumor xenografts. Eur J Nucl Med Mol Imaging. 2020 Apr;47(4):980-990. doi: 10.1007/s00259-019-04673-1. Epub 2020 Jan 7. PMID: 31912256; PMCID: PMC7075859. 2. Mehta RK, Pal S, Kondapi K, Sitto M, Dewar C, Devasia T, Schipper MJ, Thomas DG, Basrur V, Pai MP, Morishima Y, Osawa Y, Pratt WB, Lawrence TS, Nyati MK. Low-Dose Hsp90 Inhibitor Selectively Radiosensitizes HNSCC and Pancreatic Xenografts. Clin Cancer Res. 2020 Oct 1;26(19):5246-5257. doi: 10.1158/1078-0432.CCR-19-3102. Epub 2020 Jul 27. PMID: 32718999; PMCID: PMC7541797.

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Enhanced Therapeutic Effects of 177Lu-DOTA-M5A in Combination with Heat Shock Protein 90 Inhibitor Onalespib in Colorectal Cancer Xenografts. Cancers (Basel). 2023 Aug 24;15(17):4239. doi: 10.3390/cancers15174239. PMID: 37686514; PMCID: PMC10486833. 4: Mooradian MJ, Cleary JM, Giobbie-Hurder A, Darville LNF, Parikh A, Buchbinder EI, Cohen JV, Lawrence DP, Shapiro GI, Keer H, Chen HX, Ivy SP, Smalley KSM, Koomen JM, Sullivan RJ. Dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF-mutant solid tumors. Cancer. 2023 Jun 15;129(12):1904-1918. doi: 10.1002/cncr.34730. Epub 2023 Apr 11. PMID: 37042037; PMCID: PMC10793106. 5: Diabate O, Cisse C, Sangare M, Soremekun O, Fatumo S, Shaffer JG, Doumbia S, Wele M. Identification of promising high-affinity inhibitors of SARS-CoV-2 main protease from African Natural Products Databases by Virtual Screening. Res Sq [Preprint]. 2023 Mar 24:rs.3.rs-2673755. doi: 10.21203/rs.3.rs-2673755/v1. PMID: 36993208; PMCID: PMC10055610. 6: David GM, Maria Del Pilar BC, Cristina MR. New therapies in non-small cell lung cancer with EGFR exon 20 insertion mutations. J Oncol Pharm Pract. 2023 Jun;29(4):934-943. doi: 10.1177/10781552231162545. Epub 2023 Mar 14. PMID: 36916182. 7: Mainwaring OJ, Weishaupt H, Zhao M, Rosén G, Borgenvik A, Breinschmid L, Verbaan AD, Richardson S, Thompson D, Clifford SC, Hill RM, Annusver K, Sundström A, Holmberg KO, Kasper M, Hutter S, Swartling FJ. ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors. Nat Commun. 2023 Mar 3;14(1):1221. doi: 10.1038/s41467-023-36847-9. PMID: 36869047; PMCID: PMC9984535. 8: Cools R, Vermeulen K, Narykina V, Leitao RCF, Bormans G. Radiosynthesis and preclinical evaluation of [11C]SNX-ab as an Hsp90α,β isoform- selective PET probe for in vivo brain and tumour imaging. EJNMMI Radiopharm Chem. 2023 Jan 30;8(1):2. doi: 10.1186/s41181-023-00189-0. PMID: 36715827; PMCID: PMC9886718. 9: Kuroyanagi G, Tokuda H, Fujita K, Kawabata T, Sakai G, Kim W, Hioki T, Tachi J, Matsushima-Nishiwaki R, Otsuka T, Iida H, Kozawa O. Upregulation of TGF-β- induced HSP27 by HSP90 inhibitors in osteoblasts. BMC Musculoskelet Disord. 2022 May 26;23(1):495. doi: 10.1186/s12891-022-05419-1. PMID: 35619094; PMCID: PMC9134601. 10: Mohajershojai T, Jha P, Boström A, Frejd FY, Yazaki PJ, Nestor M. In Vitro Characterization of 177Lu-DOTA-M5A Anti-Carcinoembryonic Antigen Humanized Antibody and HSP90 Inhibition for Potentiated Radioimmunotherapy of Colorectal Cancer. Front Oncol. 2022 Mar 31;12:849338. doi: 10.3389/fonc.2022.849338. PMID: 35433442; PMCID: PMC9010075. 11: Colunga Biancatelli RML, Solopov P, Dimitropoulou C, Gregory B, Day T, Catravas JD. The Heat Shock Protein 90 Inhibitor, AT13387, Protects the Alveolo- Capillary Barrier and Prevents HCl-Induced Chronic Lung Injury and Pulmonary Fibrosis. Cells. 2022 Mar 19;11(6):1046. doi: 10.3390/cells11061046. PMID: 35326496; PMCID: PMC8946990. 12: Xu J, Wu PJ, Lai TH, Sharma P, Canella A, Welker AM, Beattie CE, Elder JB, Easley M, Lonser R, Jacob NK, Pietrzak M, Timmers CM, Lang F, Sampath D, Puduvalli VK. Disruption of DNA Repair and Survival Pathways through Heat Shock Protein Inhibition by Onalespib to Sensitize Malignant Gliomas to Chemoradiation Therapy. Clin Cancer Res. 2022 May 2;28(9):1979-1990. doi: 10.1158/1078-0432.CCR-20-0468. PMID: 35140124; PMCID: PMC9064967. 13: Ewers KM, Patil S, Kopp W, Thomale J, Quilitz T, Magerhans A, Wang X, Hessmann E, Dobbelstein M. HSP90 Inhibition Synergizes with Cisplatin to Eliminate Basal-like Pancreatic Ductal Adenocarcinoma Cells. Cancers (Basel). 2021 Dec 7;13(24):6163. doi: 10.3390/cancers13246163. PMID: 34944784; PMCID: PMC8699576. 14: Konstantinopoulos PA, Cheng SC, Supko JG, Polak M, Wahner-Hendrickson AE, Ivy SP, Bowes B, Sawyer H, Basada P, Hayes M, Curtis J, Horowitz N, Wright AA, Campos SM, Ivanova EV, Paweletz CP, Palakurthi S, Liu JF, D'Andrea AD, Gokhale PC, Chowdhury D, Matulonis UA, Shapiro GI. Combined PARP and HSP90 inhibition: preclinical and Phase 1 evaluation in patients with advanced solid tumours. Br J Cancer. 2022 Apr;126(7):1027-1036. doi: 10.1038/s41416-021-01664-8. Epub 2021 Dec 9. PMID: 34887522; PMCID: PMC8980096. 15: Vermeulen K, Cools R, Briard E, Auberson Y, Schoepfer J, Koole M, Cawthorne C, Bormans G. Preclinical Evaluation of [11C]YC-72-AB85 for In Vivo Visualization of Heat Shock Protein 90 in Brain and Cancer with Positron Emission Tomography. ACS Chem Neurosci. 2021 Oct 20;12(20):3915-3927. doi: 10.1021/acschemneuro.1c00508. Epub 2021 Oct 1. PMID: 34597516. 16: Klemke L, Fehlau CF, Winkler N, Toboll F, Singh SK, Moll UM, Schulz- Heddergott R. The Gain-of-Function p53 R248W Mutant Promotes Migration by STAT3 Deregulation in Human Pancreatic Cancer Cells. Front Oncol. 2021 Jun 11;11:642603. doi: 10.3389/fonc.2021.642603. PMID: 34178628; PMCID: PMC8226097. 17: Riess JW, Reckamp KL, Frankel P, Longmate J, Kelly KA, Gandara DR, Weipert CM, Raymond VM, Keer HN, Mack PC, Newman EM, Lara PN Jr. 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. Epub 2021 May 15. PMID: 34140248; PMCID: PMC9239707. 18: Kuroyanagi G, Kawabata T, Tokuda H, Fujita K, Matsushima-Nishiwaki R, Sakai G, Tachi J, Hioki T, Kim W, Iida H, Otsuka T, Kozawa O. Attenuation by HSP90 inhibitors of EGF-elicited migration of osteoblasts: involvement of p44/p42 MAP kinase. Connect Tissue Res. 2022 Jul;63(4):359-369. doi: 10.1080/03008207.2021.1939323. Epub 2021 Jun 8. PMID: 34100663. 19: Gulla A, Kazlauskas E, Liang H, Strupas K, Petrauskas V, Matulis D, Eshleman JR. Heat Shock Protein 90 Inhibitor Effects on Pancreatic Cancer Cell Cultures. Pancreas. 2021 Apr 1;50(4):625-632. doi: 10.1097/MPA.0000000000001807. PMID: 33939678. 20: Naz S, Leiker AJ, Choudhuri R, Preston O, Sowers AL, Gohain S, Gamson J, Mathias A, Van Waes C, Cook JA, Mitchell JB. Pharmacological Inhibition of HSP90 Radiosensitizes Head and Neck Squamous Cell Carcinoma Xenograft by Inhibition of DNA Damage Repair, Nucleotide Metabolism, and Radiation-Induced Tumor Vasculogenesis. Int J Radiat Oncol Biol Phys. 2021 Aug 1;110(5):1295-1305. doi: 10.1016/j.ijrobp.2021.03.048. Epub 2021 Apr 7. PMID: 33838214; PMCID: PMC8286306.