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MedKoo Cat#: 206040 | Name: AZD3965
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Description:

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

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.

Chemical Structure

AZD3965
AZD3965
CAS#1448671-31-5

Theoretical Analysis

MedKoo Cat#: 206040

Name: AZD3965

CAS#: 1448671-31-5

Chemical Formula: C21H24F3N5O5S

Exact Mass: 515.1450

Molecular Weight: 515.51

Elemental Analysis: C, 48.93; H, 4.69; F, 11.06; N, 13.59; O, 15.52; S, 6.22

Price and Availability

Size Price Availability Quantity
5mg USD 150.00 Ready to ship
10mg USD 250.00 Ready to ship
25mg USD 450.00 Ready to ship
50mg USD 750.00 Ready to ship
100mg USD 1,250.00 Ready to ship
200mg USD 2,050.00 Ready to ship
500mg USD 4,250.00 Ready to ship
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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<0.0001; 2 way ANOVA), although tumour regression was not seen, consistent with AZD3965 only targeting the hypoxic fraction of the tumour. Analysis of lactate concentration at sacrifice confirmed that the reduced tumor growth rate was accompanied by a significant increase in intra-tumor lactate (Figure 2B; p=0.0038). Reference: Clin Cancer Res. 2014 Feb 15;20(4):926-937. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929348/
Solvent mg/mL mM
Solubility
DMSO 36.0 69.83
Ethanol 100.0 193.98
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 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.

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:
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.
1: Grønningsæter IS, Reikvam H, Aasebø E, Bartaula-Brevik S, Tvedt TH, Bruserud Ø, Hatfield KJ. Targeting Cellular Metabolism in Acute Myeloid Leukemia and The Role of Patient Heterogeneity. Cells. 2020 May 7;9(5):E1155. doi: 10.3390/cells9051155. PMID: 32392896. 2: Puri S, Juvale K. Monocarboxylate transporter 1 and 4 inhibitors as potential therapeutics for treating solid tumours: A review with structure-activity relationship insights. Eur J Med Chem. 2020 May 1;199:112393. doi: 10.1016/j.ejmech.2020.112393. Epub ahead of print. PMID: 32388280. 3: McNeillis R, Greystoke A, Walton J, Bacon C, Keun H, Siskos A, Petrides G, Leech N, Jenkinson F, Bowron A, Halford S, Plummer R. Correction: A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono- carboxylase transporter 1 inhibitor AZD3965. Br J Cancer. 2020 Apr;122(8):1272. doi: 10.1038/s41416-020-0801-2. Erratum for: Br J Cancer. 2020 Apr;122(8):1141-1145. PMID: 32203218; PMCID: PMC7156454. 4: McNeillis R, Greystoke A, Walton J, Bacon C, Keun H, Siskos A, Petrides G, Leech N, Jenkinson F, Bowron A, Halford S, Plummer R. A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965. Br J Cancer. 2020 Apr;122(8):1141-1145. doi: 10.1038/s41416-020-0727-8. Epub 2020 Feb 20. Erratum in: Br J Cancer. 2020 Mar 12;: PMID: 32076124; PMCID: PMC7156442. 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. 6: Huang CY, Hsu LH, Chen CY, Chang GC, Chang HW, Hung YM, Liu KJ, Kao SH. Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy. Cancers (Basel). 2020 Jan 10;12(1):181. doi: 10.3390/cancers12010181. PMID: 31936895; PMCID: PMC7017237. 7: 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. 8: Follman KE, Morris ME. Treatment of γ-Hydroxybutyric Acid and γ-Butyrolactone Overdose with Two Potent Monocarboxylate Transporter 1 Inhibitors, AZD3965 and AR-C155858. J Pharmacol Exp Ther. 2019 Jul;370(1):84-91. doi: 10.1124/jpet.119.256503. Epub 2019 Apr 22. PMID: 31010842; PMCID: PMC6548980. 9: Afonso J, Pinto T, Simões-Sousa S, Schmitt F, Longatto-Filho A, Pinheiro C, Marques H, Baltazar F. Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma - MCT1 as potential target in diffuse large B cell lymphoma. Cell Oncol (Dordr). 2019 Jun;42(3):303-318. doi: 10.1007/s13402-019-00426-2. Epub 2019 Feb 21. PMID: 30790227. 10: Guan X, Rodriguez-Cruz V, Morris ME. Cellular Uptake of MCT1 Inhibitors AR-C155858 and AZD3965 and Their Effects on MCT-Mediated Transport of L-Lactate in Murine 4T1 Breast Tumor Cancer Cells. AAPS J. 2019 Jan 7;21(2):13. doi: 10.1208/s12248-018-0279-5. PMID: 30617815; PMCID: PMC6466617. 11: Behrends V, Giskeødegård GF, Bravo-Santano N, Letek M, Keun HC. Acetaminophen cytotoxicity in HepG2 cells is associated with a decoupling of glycolysis from the TCA cycle, loss of NADPH production, and suppression of anabolism. Arch Toxicol. 2019 Feb;93(2):341-353. doi: 10.1007/s00204-018-2371-0. Epub 2018 Dec 14. PMID: 30552463. 12: Mehibel M, Ortiz-Martinez F, Voelxen N, Boyers A, Chadwick A, Telfer BA, Mueller-Klieser W, West CM, Critchlow SE, Williams KJ, Stratford IJ. Statin- induced metabolic reprogramming in head and neck cancer: a biomarker for targeting monocarboxylate transporters. Sci Rep. 2018 Nov 14;8(1):16804. doi: 10.1038/s41598-018-35103-1. PMID: 30429503; PMCID: PMC6235971. 13: Quanz M, Bender E, Kopitz C, Grünewald S, Schlicker A, Schwede W, Eheim A, Toschi L, Neuhaus R, Richter C, Toedling J, Merz C, Lesche R, Kamburov A, Siebeneicher H, Bauser M, Hägebarth A. Preclinical Efficacy of the Novel Monocarboxylate Transporter 1 Inhibitor BAY-8002 and Associated Markers of Resistance. Mol Cancer Ther. 2018 Nov;17(11):2285-2296. doi: 10.1158/1535-7163.MCT-17-1253. Epub 2018 Aug 16. PMID: 30115664. 14: Hashimoto M, Girardi E, Eichner R, Superti-Furga G. Detection of Chemical Engagement of Solute Carrier Proteins by a Cellular Thermal Shift Assay. ACS Chem Biol. 2018 Jun 15;13(6):1480-1486. doi: 10.1021/acschembio.8b00270. Epub 2018 Jun 6. PMID: 29851333; PMCID: PMC6067815. 15: Guan X, Ruszaj D, Morris ME. Development and validation of a liquid chromatography tandem mass spectrometry assay for AZD3965 in mouse plasma and tumor tissue: Application to pharmacokinetic and breast tumor xenograft studies. J Pharm Biomed Anal. 2018 Jun 5;155:270-275. doi: 10.1016/j.jpba.2018.03.061. Epub 2018 Mar 31. PMID: 29674138; PMCID: PMC6158793. 16: 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. 17: Beloueche-Babari M, Wantuch S, Casals Galobart T, Koniordou M, Parkes HG, Arunan V, Chung YL, Eykyn TR, Smith PD, Leach MO. MCT1 Inhibitor AZD3965 Increases Mitochondrial Metabolism, Facilitating Combination Therapy and Noninvasive Magnetic Resonance Spectroscopy. Cancer Res. 2017 Nov 1;77(21):5913-5924. doi: 10.1158/0008-5472.CAN-16-2686. Epub 2017 Sep 18. PMID: 28923861; PMCID: PMC5669455. 18: Noble RA, Bell N, Blair H, Sikka A, Thomas H, Phillips N, Nakjang S, Miwa S, Crossland R, Rand V, Televantou D, Long A, Keun HC, Bacon CM, Bomken S, Critchlow SE, Wedge SR. Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma. Haematologica. 2017 Jul;102(7):1247-1257. doi: 10.3324/haematol.2016.163030. Epub 2017 Apr 6. PMID: 28385782; PMCID: PMC5566036. 19: Wang C, Wen Z, Xie J, Zhao Y, Zhao L, Zhang S, Liu Y, Xue Y, Shi M. MACC1 mediates chemotherapy sensitivity of 5-FU and cisplatin via regulating MCT1 expression in gastric cancer. Biochem Biophys Res Commun. 2017 Apr 8;485(3):665-671. doi: 10.1016/j.bbrc.2017.02.096. Epub 2017 Feb 21. PMID: 28235486. 20: Van Hée VF, Labar D, Dehon G, Grasso D, Grégoire V, Muccioli GG, Frédérick R, Sonveaux P. Radiosynthesis and validation of (±)-[18F]-3-fluoro-2-hydroxypropionate ([18F]-FLac) as a PET tracer of lactate to monitor MCT1-dependent lactate uptake in tumors. Oncotarget. 2017 Apr 11;8(15):24415-24428. doi: 10.18632/oncotarget.14705. PMID: 28107190; PMCID: PMC5421858.