WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H206040
CAS#: 1448671-31-5
Description: AZD3965 is a selective inhibitor of monocarboxylate transporter 1 (MCT1) with a binding affinity of 1.6 nM, is 6 fold selective over MCT2 and does not inhibit MCT4 at 10 μM. In vivo, AZD3965 is well tolerated and induces a dose and time dependent accumulation of lactate in the tumours, suppresses tumour growth and in the Raji model potentiates the effects of Rituxan, doxorubicin and bendamustine. The selective inhibition of lactate transport by the MCT1 inhibitor AZD3965 offers an novel mechanism for targeting the metabolic phenotype in tumours that preferentially express MCT1.
Hodoodo Cat#: H206040
Name: AZD3965
CAS#: 1448671-31-5
Chemical Formula: C21H24F3N5O5S
Exact Mass: 515.15
Molecular Weight: 515.506
Elemental Analysis: C, 48.93; H, 4.69; F, 11.06; N, 13.59; O, 15.52; S, 6.22
Related CAS #: 1448671-31-5 733809-45-5
Synonym: AZD3965; AZD-3965; AZD 3965.
IUPAC/Chemical Name: (S)-5-(4-hydroxy-4-methylisoxazolidine-2-carbonyl)-1-isopropyl-3-methyl-6-((3-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
InChi Key: PRNXOFBDXNTIFG-FQEVSTJZSA-N
InChi Code: InChI=1S/C21H24F3N5O5S/c1-9(2)29-18-14(16(30)27(5)19(29)32)13(17(31)28-7-20(4,33)8-34-28)12(35-18)6-11-10(3)25-26-15(11)21(22,23)24/h9,33H,6-8H2,1-5H3,(H,25,26)/t20-/m0/s1
SMILES Code: O=C1N(C(C)C)C2=C(C(C(N3OC[C@@](C)(O)C3)=O)=C(CC4=C(C(F)(F)F)NN=C4C)S2)C(N1C)=O.
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: AZD3965 sensitivity varied in vitro and was highest in hypoxia. Resistance in hypoxia was associated with increased MCT4 expression. In vivo, AZD3965 reduced tumor growth and increased intra-tumor lactate. In the tissue microarray, high MCT1 expression was associated with worse prognosis (p=0.014). MCT1 and hypoxia marker CA IX expression in the absence of MCT4 was observed in 21% of SCLC tumor
| Biological target: | AZD3965 is a potent, selective and orally available monocarboxylate transporter 1 (MCT1) inhibitor with a binding affinity of 1.6 nM, 6-fold selective over MCT2. |
| In vitro activity: | A panel of seven SCLC cell lines was constructed to reflect the mutations in TP53, RB1 and MYC family genes that are common in SCLC (Supplemental Table 1). To assess the efficacy of AZD3965 (Supplemental Figure 1) these cell lines were cultured under normoxic or hypoxic (1% O2) conditions and exposed for 72h to 8 nM AZD3965, a concentration of AZD3965 which inhibited MCT1 activity (data not shown). Generally, cells cultured under hypoxic conditions were more sensitive to AZD3965 than their normoxic counterparts (Figure 1A). There was a wide range of responses of hypoxic cells to AZD3965, with COR-L103, NCI-H526 and NCI-H1048 being relatively sensitive and DMS114, DMS79 and NCI-H146 relatively resistant. NCI-H526, NCI-H1048, NCI-H524 and NCI-H146 cells also demonstrated a reproducible response to AZD3965 under normoxic conditions. Reference: Clin Cancer Res. 2014 Feb 15;20(4):926-937. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929348/ |
| In vivo activity: | COR-L103 tumor bearing mice were treated with 100 mg/kg AZD3965 or vehicle BID for 21 days and the tumor volume monitored. Pharmacokinetic analysis demonstrated that 100 mg/kg AZD3965 BID resulted in concentrations of free AZD3965 predicted to inhibit lactate transport (data not shown). AZD3965 treatment significantly reduced the growth of COR-L103 tumors (Figure 2A – p |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 36.0 | 69.83 | |
| Ethanol | 100.0 | 193.98 |
The following data is based on the product molecular weight 515.51 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. Polański R, Hodgkinson CL, Fusi A, Nonaka D, Priest L, Kelly P, Trapani F, Bishop PW, White A, Critchlow SE, Smith PD, Blackhall F, Dive C, Morrow CJ. Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin Cancer Res. 2014 Feb 15;20(4):926-937. doi: 10.1158/1078-0432.CCR-13-2270. Epub 2013 Nov 25. PMID: 24277449; PMCID: PMC3929348. 2. Curtis NJ, Mooney L, Hopcroft L, Michopoulos F, Whalley N, Zhong H, Murray C, Logie A, Revill M, Byth KF, Benjamin AD, Firth MA, Green S, Smith PD, Critchlow SE. Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt's lymphoma anti-tumor activity. Oncotarget. 2017 May 25;8(41):69219-69236. doi: 10.18632/oncotarget.18215. PMID: 29050199; PMCID: PMC5642474. 3. Polański R, Hodgkinson CL, Fusi A, Nonaka D, Priest L, Kelly P, Trapani F, Bishop PW, White A, Critchlow SE, Smith PD, Blackhall F, Dive C, Morrow CJ. Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin Cancer Res. 2014 Feb 15;20(4):926-937. doi: 10.1158/1078-0432.CCR-13-2270. Epub 2013 Nov 25. PMID: 24277449; PMCID: PMC3929348. 4. Guan X, Morris ME. Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition. Pharm Res. 2019 Dec 10;37(1):5. doi: 10.1007/s11095-019-2735-z. PMID: 31823112. |
| In vitro protocol: | 1. Polański R, Hodgkinson CL, Fusi A, Nonaka D, Priest L, Kelly P, Trapani F, Bishop PW, White A, Critchlow SE, Smith PD, Blackhall F, Dive C, Morrow CJ. Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin Cancer Res. 2014 Feb 15;20(4):926-937. doi: 10.1158/1078-0432.CCR-13-2270. Epub 2013 Nov 25. PMID: 24277449; PMCID: PMC3929348. 2. Curtis NJ, Mooney L, Hopcroft L, Michopoulos F, Whalley N, Zhong H, Murray C, Logie A, Revill M, Byth KF, Benjamin AD, Firth MA, Green S, Smith PD, Critchlow SE. Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt's lymphoma anti-tumor activity. Oncotarget. 2017 May 25;8(41):69219-69236. doi: 10.18632/oncotarget.18215. PMID: 29050199; PMCID: PMC5642474. |
| In vivo protocol: | 1. Polański R, Hodgkinson CL, Fusi A, Nonaka D, Priest L, Kelly P, Trapani F, Bishop PW, White A, Critchlow SE, Smith PD, Blackhall F, Dive C, Morrow CJ. Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin Cancer Res. 2014 Feb 15;20(4):926-937. doi: 10.1158/1078-0432.CCR-13-2270. Epub 2013 Nov 25. PMID: 24277449; PMCID: PMC3929348. 2. Guan X, Morris ME. Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition. Pharm Res. 2019 Dec 10;37(1):5. doi: 10.1007/s11095-019-2735-z. PMID: 31823112. |
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5: Beloueche-Babari M, Casals Galobart T, Delgado-Goni T, Wantuch S, Parkes HG, Tandy D, Harker JA, Leach MO. Monocarboxylate transporter 1 blockade with AZD3965 inhibits lipid biosynthesis and increases tumour immune cell infiltration. Br J Cancer. 2020 Mar;122(6):895-903. doi: 10.1038/s41416-019-0717-x. Epub 2020 Jan 15. PMID: 31937921; PMCID: PMC7078321.
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