WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 406841
Description: A-1331852 is a potent BCL-XL-selective inhibitor. BCL-XL is the major antiapoptotic survival protein and may be a novel therapeutic target in CML. BCL-XL-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax. A-1331852 may have potential as an improved cancer therapeutic.
MedKoo Cat#: 406841
Chemical Formula: C38H38N6O3S
Exact Mass: 658.2726
Molecular Weight: 658.82
Elemental Analysis: C, 69.28; H, 5.81; N, 12.76; O, 7.29; S, 4.87
Synonym: A-1331852; A 1331852; A1331852
IUPAC/Chemical Name: 3-(1-(((3r,5r,7r)-adamantan-1-yl)methyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acid
InChi Key: QCQQONWEDCOTBV-UHFFFAOYSA-N
InChi Code: InChI=1S/C38H38N6O3S/c1-22-29(19-39-44(22)21-38-16-23-13-24(17-38)15-25(14-23)18-38)27-9-10-33(41-34(27)36(46)47)43-12-11-26-5-4-6-28(30(26)20-43)35(45)42-37-40-31-7-2-3-8-32(31)48-37/h2-10,19,23-25H,11-18,20-21H2,1H3,(H,46,47)(H,40,42,45)
SMILES Code: CC1=C(C=NN1CC23CC4CC(C2)CC(C4)C3)C5=C(N=C(C=C5)N6CCC7=CC=CC(=C7C6)C(=O)NC8=NC9=CC=CC=C9S8)C(=O)O
Appearance: 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
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
|Biological target:||A-1331852 is a BCL-XL selective inhibitor with a Ki of less than 10 pM.|
|In vitro activity:||The cell-killing efficacy of A-1331852 against MOLT-4 cells was improved by 10- to 30-fold relative to the cyclohexane 12, while maintaining selectivity against the RS4;11 cell line. Thus, A-1331852 exhibited a 6 nM EC50 against the MOLT-4 cell line, a level of in vitro efficacy 20-fold more potent than our previously disclosed tool compound A-1155463. The mechanism-based effects of A-1331852 in MOLT-4 cells were rigorously established, as reported previously. Specifically, treatment of these tumor cells with A-1331852 disrupted BCL-XL:BIM complexes and induced classical features of apoptosis including cytochrome c release, caspase-3/-7 activation, and externalization of phosphatidylserine as determined by flow cytometric evaluation of Annexin-V staining. Reference: ACS Med Chem Lett. 2020 Oct 8; 11(10): 1829–1836. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549103/|
|In vivo activity:||In NSG mice intraperitoneally injected with SNK6 cells (SNK6-IP mice), a significant delay in tumor development was observed after treatment with A-1331852 compared with vehicle-treated mice, with median tumor latencies of 56 days and 37 days posttransplant, respectively (P = .0002) (Figure 4A). Similarly, in SNK6-SC–bearing mice, A-1331852 treatment significantly delayed tumor growth (median tumor latency of 56 days compared with vehicle-treated mice (37 days) (P = .022)) (Figure 4B). In contrast, A-1331852 was ineffective at delaying tumor growth in mice transplanted with SNT15 cells (Figure 4C) or MEC04 cells (Figure 4D). Following drug treatment (day 14), there was a marked decrease in platelet numbers, consistent with successful administration of the drug with BCL-XL inhibition causing on-target thrombocytopenia (Figure 4A,D).59 As expected, the platelet counts rebounded to pretreatment levels by the time of sacrifice (days 34-62 posttransplant). Reference: Blood Adv. 2020 Oct 13; 4(19): 4775–4787. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556124/|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
|DMF:PBS (pH 7.2) (1:3)||0.25||0.38|
The following data is based on the product molecular weight 658.82 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. Wang L, Doherty GA, Judd AS, Tao ZF, Hansen TM, Frey RR, Song X, Bruncko M, Kunzer AR, Wang X, Wendt MD, Flygare JA, Catron ND, Judge RA, Park CH, Shekhar S, Phillips DC, Nimmer P, Smith ML, Tahir SK, Xiao Y, Xue J, Zhang H, Le PN, Mitten MJ, Boghaert ER, Gao W, Kovar P, Choo EF, Diaz D, Fairbrother WJ, Elmore SW, Sampath D, Leverson JD, Souers AJ. Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-XL Inhibitor. ACS Med Chem Lett. 2020 Mar 30;11(10):1829-1836. doi: 10.1021/acsmedchemlett.9b00568. PMID: 33062160; PMCID: PMC7549103. 3. Sejic N, George LC, Tierney RJ, Chang C, Kondrashova O, MacKinnon RN, Lan P, Bell AI, Lessene G, Long HM, Strasser A, Shannon-Lowe C, Kelly GL. BCL-XL inhibition by BH3-mimetic drugs induces apoptosis in models of Epstein-Barr virus-associated T/NK-cell lymphoma. Blood Adv. 2020 Oct 13;4(19):4775-4787. doi: 10.1182/bloodadvances.2020002446. PMID: 33017468; PMCID: PMC7556124.|
|In vitro protocol:||1. Wang L, Doherty GA, Judd AS, Tao ZF, Hansen TM, Frey RR, Song X, Bruncko M, Kunzer AR, Wang X, Wendt MD, Flygare JA, Catron ND, Judge RA, Park CH, Shekhar S, Phillips DC, Nimmer P, Smith ML, Tahir SK, Xiao Y, Xue J, Zhang H, Le PN, Mitten MJ, Boghaert ER, Gao W, Kovar P, Choo EF, Diaz D, Fairbrother WJ, Elmore SW, Sampath D, Leverson JD, Souers AJ. Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-XL Inhibitor. ACS Med Chem Lett. 2020 Mar 30;11(10):1829-1836. doi: 10.1021/acsmedchemlett.9b00568. PMID: 33062160; PMCID: PMC7549103.|
|In vivo protocol:||1. Sejic N, George LC, Tierney RJ, Chang C, Kondrashova O, MacKinnon RN, Lan P, Bell AI, Lessene G, Long HM, Strasser A, Shannon-Lowe C, Kelly GL. BCL-XL inhibition by BH3-mimetic drugs induces apoptosis in models of Epstein-Barr virus-associated T/NK-cell lymphoma. Blood Adv. 2020 Oct 13;4(19):4775-4787. doi: 10.1182/bloodadvances.2020002446. PMID: 33017468; PMCID: PMC7556124.|
1: Leverson JD. Chemical parsing: Dissecting cell dependencies with a toolkit of selective BCL-2 family inhibitors. Mol Cell Oncol. 2015 May 26;3(1):e1050155. doi: 10.1080/23723556.2015.1050155. eCollection 2016 Jan. PubMed PMID: 27308564; PubMed Central PMCID: PMC4845185.
2: Lucas CM, Milani M, Butterworth M, Carmell N, Scott LJ, Clark RE, Cohen GM, Varadarajan S. High CIP2A levels correlate with an antiapoptotic phenotype that can be overcome by targeting BCL-XL in chronic myeloid leukemia. Leukemia. 2016 Jun;30(6):1273-81. doi: 10.1038/leu.2016.42. Epub 2016 Feb 29. PubMed PMID: 26987906; PubMed Central PMCID: PMC4895185.
3: Butterworth M, Pettitt A, Varadarajan S, Cohen GM. BH3 profiling and a toolkit of BH3-mimetic drugs predict anti-apoptotic dependence of cancer cells. Br J Cancer. 2016 Mar 15;114(6):638-41. doi: 10.1038/bjc.2016.49. Epub 2016 Mar 8. PubMed PMID: 26954718; PubMed Central PMCID: PMC4800304.
4: Punnoose EA, Leverson JD, Peale F, Boghaert ER, Belmont LD, Tan N, Young A, Mitten M, Ingalla E, Darbonne WC, Oleksijew A, Tapang P, Yue P, Oeh J, Lee L, Maiga S, Fairbrother WJ, Amiot M, Souers AJ, Sampath D. Expression Profile of BCL-2, BCL-XL, and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in Multiple Myeloma Models. Mol Cancer Ther. 2016 May;15(5):1132-44. doi: 10.1158/1535-7163.MCT-15-0730. Epub 2016 Mar 3. PubMed PMID: 26939706.
5: Leverson JD, Phillips DC, Mitten MJ, Boghaert ER, Diaz D, Tahir SK, Belmont LD, Nimmer P, Xiao Y, Ma XM, Lowes KN, Kovar P, Chen J, Jin S, Smith M, Xue J, Zhang H, Oleksijew A, Magoc TJ, Vaidya KS, Albert DH, Tarrant JM, La N, Wang L, Tao ZF, Wendt MD, Sampath D, Rosenberg SH, Tse C, Huang DC, Fairbrother WJ, Elmore SW, Souers AJ. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci Transl Med. 2015 Mar 18;7(279):279ra40. doi: 10.1126/scitranslmed.aaa4642. PubMed PMID: 25787766.