Debio-0932
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MedKoo CAT#: 205737

CAS#: 1061318-81-7

Description: Debio 0932, also known as CUDC-305, is a novel heat shock protein 90 (HSP90) inhibitor with strong affinity for HSP90 alpha/beta, high oral bioavailability and potent anti-proliferative activity against a broad range of cancer cell lines (with a mean IC50 of 220 nmol/L), including many non-small cell lung cancer (NSCLC) cell lines which are resistant to standard-of-care (SOC) agents. Debio 0932 potently inhibits tumour growth in subcutaneous xenograft models of a number of solid and haematological malignancies, including models of NSCLC which harbour mutations conferring acquired or primary erlotinib resistance.

Chemical Structure

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Debio-0932
CAS# 1061318-81-7
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 205737
Name: Debio-0932
CAS#: 1061318-81-7
Chemical Formula: C22H30N6O2S
Exact Mass: 442.22
Molecular Weight: 442.580
Elemental Analysis: C, 59.70; H, 6.83; N, 18.99; O, 7.23; S, 7.25

Price and Availability

Size Price Availability Quantity
5mg USD 120 Ready to ship
10mg USD 200 Ready to ship
25mg USD 400 Ready to ship
50mg USD 800 Ready to ship
100mg USD 1350 Ready to ship
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Synonym: Debio0932; Debio-0932; Debio 0932; CUDC305; CUDC-305; CUDC 305.

IUPAC/Chemical Name: 2-((6-(dimethylamino)benzo[d][1,3]dioxol-5-yl)thio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine

InChi Key: RVJIQAYFTOPTKK-UHFFFAOYSA-N

InChi Code: InChI=1S/C22H30N6O2S/c1-22(2,3)12-24-8-9-28-14-6-7-25-20(23)19(14)26-21(28)31-18-11-17-16(29-13-30-17)10-15(18)27(4)5/h6-7,10-11,24H,8-9,12-13H2,1-5H3,(H2,23,25)

SMILES Code: NC1=NC=CC2=C1N=C(SC3=C(N(C)C)C=C(OCO4)C4=C3)N2CCNCC(C)(C)C

Appearance: white to off-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: In vitro antitumor activity: Scientists from Curis, Inc tested the growth inhibitory effects of CUDC-305 against a total of 40 human cancer cell lines, including 34 solid and 6 hematologic tumor–derived lines. CUDC-305 inhibited the proliferation of these cancer cell lines with an IC50, ranging from 40 to 900 nmol/L (mean IC50, 220 nmol/L).  CUDC-305 shows high affinity for HSP90alpha/beta (IC(50), approximately 100 nmol/L) and HSP90 complex derived from cancer cells (IC(50), 48.8 nmol/L). CUDC-305 exhibits high oral bioavailability (96.0%) and selective retention in tumor (half-life, 20.4 hours) compared with normal tissues. Furthermore, CUDC-305 can cross blood-brain barrier and reach therapeutic levels in brain tissue. CUDC-305 exhibits dose-dependent antitumor activity in an s.c. xenograft model of U87MG glioblastoma and significantly prolongs animal survival in U87MG orthotopic model. CUDC-305 also displays potent antitumor activity in animal models of erlotinib-resistant non-small cell lung cancer and induces tumor regression in animal models of MDA-MB-468 breast cancer and MV4-11 acute myelogenous leukemia. Correlating with its efficacy in these various tumor models, CUDC-305 robustly inhibits multiple signaling pathways, including PI3K/AKT and RAF/MEK/ERK, and induces apoptosis. In combination studies, CUDC-305 enhances the antitumor activity of standard-of-care agents in breast and colorectal tumor models. CONCLUSION: CUDC-305 is a promising drug candidate for the treatment of a variety of cancers, including brain malignancies. (source: Clin Cancer Res. 2009 Jun 15;15(12):4046-57.).       

Biological target: Debio 0932 (CUDC-305) is an orally active HSP90 inhibitor, with IC50s of 100 and 103 nM for HSP90α and HSP90β, respectively.
In vitro activity: Whether HSP90 inhibition by CUDC-305 can induce degradation of oncoproteins was examined. In the HER2 overexpressing BT-474 breast cancer cells, CUDC-305 treatment reduced the levels of HER2/phosphorylated HER2 and phosphorylated HER3 and suppressed downstream AKT and RAF/MEK/ERK signaling. CUDC-305 also down-regulated survivin and cyclin D1, further supporting its proapoptotic and antiproliferative roles in cancer cells (Fig. 1B). The reduction of HSP90 client proteins was concurrent with an increase of HSP70, a marker of HSP90 inhibition. These results suggest that CUDC-305 specifically targets HSP90 and suppresses receptor tyrosine kinase signaling. To confirm its anticancer activity, the growth inhibitory effects of CUDC-305 was tested against a total of 40 human cancer cell lines, including 34 solid and 6 hematologic tumor–derived lines (Table 1 ). CUDC-305 inhibited the proliferation of these cancer cell lines with an IC50, ranging from 40 to 900 nmol/L (mean IC50, 220 nmol/L). Reference: Clin Cancer Res. 2009 Jun 15;15(12):4046-57. http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=19509149
In vivo activity: Given the therapeutically relevant exposure of CUDC-305 in brain tissue, the efficacy of the compound in the U87MG glioblastoma tumor models was tested. A single-dose PD study was first conducted to evaluate the duration of its biological effects in tumor xenografts implanted s.c. After a single oral dosing of CUDC-305 at 160 mg/kg, U87MG tumors were collected at various time points over a 48-hour period and subjected to Western blot analysis. As shown in Fig. 2B, HSP70 was induced from 3 to 48 hours after compound administration, correlating with our earlier findings of extended tumor exposure (9.4 μmol/L at 48 hours, 20-fold above IC50 in U87MG cells) after a single oral dosing of CUDC-305 at 160 mg/kg. Therefore, an every-other-day (q2d) dosing regimen was adopted for most efficacy studies. HSP90 client proteins, including p-AKT, and c-RAF were shown to be down-regulated, along with the induction of apoptosis as measured by poly(ADP-ribose) polymerase cleavage (Fig. 2B). Note that although minimal or no inhibition was observed for c-MET or total AKT in this single-dose PD study, inhibition of these HSP90 client proteins was achieved after multiple oral doses, as shown in our subsequent efficacy-PD study in the same tumor model. Reference: Clin Cancer Res. 2009 Jun 15;15(12):4046-57. http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=19509149

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 33.0 74.56

Preparing Stock Solutions

The following data is based on the product molecular weight 442.58 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.

Recalculate based on batch purity %
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:
In vitro protocol: 1. Bao R, Lai CJ, Qu H, Wang D, Yin L, Zifcak B, Atoyan R, Wang J, Samson M, Forrester J, DellaRocca S, Xu GX, Tao X, Zhai HX, Cai X, Qian C. CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy. Clin Cancer Res. 2009 Jun 15;15(12):4046-57. doi: 10.1158/1078-0432.CCR-09-0152. Epub 2009 Jun 9. PMID: 19509149. 2. Bao R, Lai CJ, Wang DG, Qu H, Yin L, Zifcak B, Tao X, Wang J, Atoyan R, Samson M, Forrester J, Xu GX, DellaRocca S, Borek M, Zhai HX, Cai X, Qian C. Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non-small cell lung cancer. Mol Cancer Ther. 2009 Dec;8(12):3296-306. doi: 10.1158/1535-7163.MCT-09-0538. PMID: 19952121.
In vivo protocol: 1. Bao R, Lai CJ, Qu H, Wang D, Yin L, Zifcak B, Atoyan R, Wang J, Samson M, Forrester J, DellaRocca S, Xu GX, Tao X, Zhai HX, Cai X, Qian C. CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy. Clin Cancer Res. 2009 Jun 15;15(12):4046-57. doi: 10.1158/1078-0432.CCR-09-0152. Epub 2009 Jun 9. PMID: 19509149. 2. Bao R, Lai CJ, Wang DG, Qu H, Yin L, Zifcak B, Tao X, Wang J, Atoyan R, Samson M, Forrester J, Xu GX, DellaRocca S, Borek M, Zhai HX, Cai X, Qian C. Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non-small cell lung cancer. Mol Cancer Ther. 2009 Dec;8(12):3296-306. doi: 10.1158/1535-7163.MCT-09-0538. PMID: 19952121.

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1: Özgür A, Kara A, Gökşen Tosun N, Tekin Ş, Gökçe İ. Debio-0932, a second generation oral Hsp90 inhibitor, induces apoptosis in MCF-7 and MDA-MB-231 cell lines. Mol Biol Rep. 2021 Apr;48(4):3439-3449. doi: 10.1007/s11033-021-06392-z. Epub 2021 May 17. PMID: 33999319.


2: Qin W, Yu F, Zhou H, Li P, Zhou F, Li HJ, He CX, Xing L, Zhou X, Zhao D, Li PQ, Jin X, Wang QS, He JH, Cao HL. Complex crystal structure determination and anti-non-small-cell lung cancer activity of the Hsp90N inhibitor Debio0932. Acta Crystallogr D Struct Biol. 2021 Jan 1;77(Pt 1):86-97. doi: 10.1107/S2059798320014990. Epub 2021 Jan 1. PMID: 33404528.


3: Meyer KJ, Caton E, Shapiro TA. Model System Identifies Kinetic Driver of Hsp90 Inhibitor Activity against African Trypanosomes and Plasmodium falciparum. Antimicrob Agents Chemother. 2018 Jul 27;62(8):e00056-18. doi: 10.1128/AAC.00056-18. PMID: 29866861; PMCID: PMC6105818.


4: Li QQ, Hao JJ, Zhang Z, Krane LS, Hammerich KH, Sanford T, Trepel JB, Neckers L, Agarwal PK. Proteomic analysis of proteome and histone post-translational modifications in heat shock protein 90 inhibition-mediated bladder cancer therapeutics. Sci Rep. 2017 Mar 15;7(1):201. doi: 10.1038/s41598-017-00143-6. PMID: 28298630; PMCID: PMC5427839.


5: Isambert N, Delord JP, Soria JC, Hollebecque A, Gomez-Roca C, Purcea D, Rouits E, Belli R, Fumoleau P. Debio0932, a second-generation oral heat shock protein (HSP) inhibitor, in patients with advanced cancer-results of a first-in- man dose-escalation study with a fixed-dose extension phase. Ann Oncol. 2015 May;26(5):1005-1011. doi: 10.1093/annonc/mdv031. Epub 2015 Feb 2. PMID: 25646368.


6: Xu XL, Sun HP, Liu F, Jia JM, Guo XK, Pan Y, Huang HZ, Zhang XJ, You QD. Discovery and Bioevaluation of Novel Pyrazolopyrimidine Analogs as Competitive Hsp90 Inhibitors Through Shape-Based Similarity Screening. Mol Inform. 2014 Apr;33(4):293-306. doi: 10.1002/minf.201300150. Epub 2014 Apr 11. PMID: 27485776.


7: Stenderup K, Rosada C, Gavillet B, Vuagniaux G, Dam TN. Debio 0932, a new oral Hsp90 inhibitor, alleviates psoriasis in a xenograft transplantation model. Acta Derm Venereol. 2014 Nov;94(6):672-6. doi: 10.2340/00015555-1838. PMID: 24604074.


8: Bao R, Lai CJ, Wang DG, Qu H, Yin L, Zifcak B, Tao X, Wang J, Atoyan R, Samson M, Forrester J, Xu GX, DellaRocca S, Borek M, Zhai HX, Cai X, Qian C. Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non-small cell lung cancer. Mol Cancer Ther. 2009 Dec;8(12):3296-306. doi: 10.1158/1535-7163.MCT-09-0538. PMID: 19952121.


9: Bao R, Lai CJ, Qu H, Wang D, Yin L, Zifcak B, Atoyan R, Wang J, Samson M, Forrester J, DellaRocca S, Xu GX, Tao X, Zhai HX, Cai X, Qian C. CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy. Clin Cancer Res. 2009 Jun 15;15(12):4046-57. doi: 10.1158/1078-0432.CCR-09-0152. Epub 2009 Jun 9. PMID: 19509149.