Acalabrutinib | ACP-196 | CAS#1420477-60-6 | BTK inhibitor

MedKoo Cat#: 206112 | Name: Acalabrutinib (ACP-196)

Description:

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

Acalabrutinib, also known as ACP-196, is an orally available inhibitor of Bruton’s tyrosine kinase (BTK) with potential antineoplastic activity. Upon administration, ACP-196 inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways. This leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK, a member of the src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in B-cell malignancies; it plays an important role in B lymphocyte development, activation, signaling, proliferation and survival.

Chemical Structure

Acalabrutinib (ACP-196)

CAS#1420477-60-6 (free base)

Theoretical Analysis

MedKoo Cat#: 206112

Name: Acalabrutinib (ACP-196)

CAS#: 1420477-60-6 (free base)

Chemical Formula: C26H23N7O2

Exact Mass: 465.1913

Molecular Weight: 465.52

Elemental Analysis: C, 67.08; H, 4.98; N, 21.06; O, 6.87

Price and Availability

Size	Price	Availability
50mg	USD 90.00	Ready to ship
100mg	USD 150.00	Ready to ship
200mg	USD 250.00	Ready to ship
500mg	USD 550.00	Ready to ship
1g	USD 950.00	Ready to ship
2g	USD 1,650.00	Ready to ship

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Related CAS #

1420477-60-6 (free base) 2242394-65-4 (maleate) 2058091-93-1 (3 hydrate) 2058091-94-2 (fumarate),2058091-96-4 (phosphate) 2058091-99-7 (citrate) 2058091-97-5 (tartrate) 2058092-05-8 (sulfate)

Synonym

ACP-196; ACP196; ACP 196; Acalabrutinib

IUPAC/Chemical Name

(S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide

InChi Key

WDENQIQQYWYTPO-IBGZPJMESA-N

InChi Code

InChI=1S/C26H23N7O2/c1-2-6-21(34)32-15-5-7-19(32)25-31-22(23-24(27)29-14-16-33(23)25)17-9-11-18(12-10-17)26(35)30-20-8-3-4-13-28-20/h3-4,8-14,16,19H,5,7,15H2,1H3,(H2,27,29)(H,28,30,35)/t19-/m0/s1

SMILES Code

O=C(NC1=NC=CC=C1)C2=CC=C(C3=C4C(N)=NC=CN4C([C@H]5N(C(C#CC)=O)CCC5)=N3)C=C2

Appearance

Yellow 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

Acalabrutinib is a potent and selective BTK (Bruton's tyrosine kinase) inhibitor. BTK is a cytoplasmic, non-receptor tyrosine kinase that transmits signals from a variety of cell-surface molecules, including the B-cell receptor (BCR) and tissue homing receptors. Genetic BTK deletion causes B-cell immunodeficiency in humans and mice, making this kinase an attractive therapeutic target for B-cell disorders. BTK inhibitors targeting B cell receptor signaling and other survival mechanism showed great promise for the treatment of chronic lymphocytic leukemia (CLL)s holds great promise. As of 2015 it is in late stage clinical trials for relapsed chronic lymphocytic leukemia. Interim results are encouraging : 95% overall response rate. It is also in another 20 clinical trials (alone and in combination) for various cancers.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#EOS61017

View CoA: current batch, Lot#BBC60324

QC Data

View QC data: current batch, Lot#EOS61017

View QC data: current batch, Lot#BBC60324

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Acalabrutinib (ACP-196) is an irreversible second-generation BTK inhibitor.

In vitro activity:

In contrast, acalabrutinib did not inhibit phagocytosis significantly at any dose. This study also performed phagocytosis assays in chamber slides, counting phagocytosing macrophages directly under the microscope. As shown in Figure 2B, 10 μM ibrutinib, but not acalabrutinib, significantly inhibited phagocytosis of rituximabopsonized CLL B cells by macrophages. These data confirm previous reports that ibrutinib inhibits antibody-dependent phagocytosis with an IC50 of 1–3 μM. Although monocytes/macrophages express BTK, the lower IC50 for ibrutinib and the fact that acalabrutinib had little effect on phagocytosis indicate that kinases situated downstream of Fcg receptors other than BTK, such as Hck, FgR or Lyn, and reported to be differentially inhibited by acalabrutinib and BTK,1 may be involved in this phenomenon. This hypothesis does, however, remain to be investigated in detail. Reference: Haematologica. 2017 Oct; 102(10): e400–e403. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622871/

In vivo activity:

Two doses of 15 mg/kg of acalabrutinib completely inhibited anaphylactic responses during moderate PSA (20 μg NP-BSA challenge) with an average maximum body temperature decline of –0.369°C and 0% mortality compared with treatment with vehicle (average maximum temperature decline of –3.678°C and 11% mortality; P = 0.0015 by 2-way ANOVA; Figure 6A). Mice receiving this dose of acalabrutinib also showed no increase in clinical score during PSA; consequently, based on scoring and core temperature, their PSA response was not significantly different from that of mice sham-sensitized with PBS instead of IgE. Two lower doses of 1.5 mg/kg of acalabrutinib provided partial protection compared with vehicle (average maximum temperature drop of –2.577°C). Reference: J Clin Invest. 2020 Sep 1; 130(9): 4759–4770. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456252/

	Solvent	mg/mL	mM
Solubility
	DMSO	81.0	174.00
	DMSO:PBS (pH 7.2) (1:1)	0.5	1.07
	DMF	25.0	53.07
	Ethanol	37.5	80.56

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 465.52 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. Series J, Garcia C, Levade M, Viaud J, Sié P, Ysebaert L, Payrastre B. Differences and similarities in the effects of ibrutinib and acalabrutinib on platelet functions. Haematologica. 2019 Nov;104(11):2292-2299. doi: 10.3324/haematol.2018.207183. Epub 2019 Feb 28. PMID: 30819914; PMCID: PMC6821604. 2. Golay J, Ubiali G, Introna M. The specific Bruton tyrosine kinase inhibitor acalabrutinib (ACP-196) shows favorable in vitro activity against chronic lymphocytic leukemia B cells with CD20 antibodies. Haematologica. 2017 Oct;102(10):e400-e403. doi: 10.3324/haematol.2017.169334. Epub 2017 Jun 22. PMID: 28642301; PMCID: PMC5622871. 3. Dispenza MC, Krier-Burris RA, Chhiba KD, Undem BJ, Robida PA, Bochner BS. Bruton's tyrosine kinase inhibition effectively protects against human IgE-mediated anaphylaxis. J Clin Invest. 2020 Sep 1;130(9):4759-4770. doi: 10.1172/JCI138448. PMID: 32484802; PMCID: PMC7456252. 4. Herman SEM, Montraveta A, Niemann CU, Mora-Jensen H, Gulrajani M, Krantz F, Mantel R, Smith LL, McClanahan F, Harrington BK, Colomer D, Covey T, Byrd JC, Izumi R, Kaptein A, Ulrich R, Johnson AJ, Lannutti BJ, Wiestner A, Woyach JA. The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia. Clin Cancer Res. 2017 Jun 1;23(11):2831-2841. doi: 10.1158/1078-0432.CCR-16-0463. Epub 2016 Nov 30. PMID: 27903679; PMCID: PMC5548968.

In vitro protocol:

In vivo protocol:

1. Dispenza MC, Krier-Burris RA, Chhiba KD, Undem BJ, Robida PA, Bochner BS. Bruton's tyrosine kinase inhibition effectively protects against human IgE-mediated anaphylaxis. J Clin Invest. 2020 Sep 1;130(9):4759-4770. doi: 10.1172/JCI138448. PMID: 32484802; PMCID: PMC7456252. 2. Herman SEM, Montraveta A, Niemann CU, Mora-Jensen H, Gulrajani M, Krantz F, Mantel R, Smith LL, McClanahan F, Harrington BK, Colomer D, Covey T, Byrd JC, Izumi R, Kaptein A, Ulrich R, Johnson AJ, Lannutti BJ, Wiestner A, Woyach JA. The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia. Clin Cancer Res. 2017 Jun 1;23(11):2831-2841. doi: 10.1158/1078-0432.CCR-16-0463. Epub 2016 Nov 30. PMID: 27903679; PMCID: PMC5548968.

1: Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR, Hillmen P, Stephens DM, Ghia P, Barrientos JC, Pagel JM, Woyach J, Johnson D, Huang J, Wang X, Kaptein A, Lannutti BJ, Covey T, Fardis M, McGreivy J, Hamdy A, Rothbaum W, Izumi R, Diacovo TG, Johnson AJ, Furman RR. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):323-32. doi: 10.1056/NEJMoa1509981. Epub 2015 Dec 7. PMID: 26641137; PMCID: PMC4862586. 2: Wu J, Zhang M, Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016 Mar 9;9:21. doi: 10.1186/s13045-016-0250-9. PMID: 26957112; PMCID: PMC4784459. 3: Barf T, Covey T, Izumi R, van de Kar B, Gulrajani M, van Lith B, van Hoek M, de Zwart E, Mittag D, Demont D, Verkaik S, Krantz F, Pearson PG, Ulrich R, Kaptein A. Acalabrutinib (ACP-196): A Covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated Selectivity and In Vivo Potency Profile. J Pharmacol Exp Ther. 2017 Nov;363(2):240-252. doi: 10.1124/jpet.117.242909. Epub 2017 Sep 7. PMID: 28882879. 4: Byrd JC, Hillmen P, Ghia P, Kater AP, Chanan-Khan A, Furman RR, O'Brien S, Yenerel MN, Illés A, Kay N, Garcia-Marco JA, Mato A, Pinilla-Ibarz J, Seymour JF, Lepretre S, Stilgenbauer S, Robak T, Rothbaum W, Izumi R, Hamdy A, Patel P, Higgins K, Sohoni S, Jurczak W. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. J Clin Oncol. 2021 Nov 1;39(31):3441-3452. doi: 10.1200/JCO.21.01210. Epub 2021 Jul 26. PMID: 34310172; PMCID: PMC8547923. 5: Hallek M, Al-Sawaf O. Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures. Am J Hematol. 2021 Dec 1;96(12):1679-1705. doi: 10.1002/ajh.26367. PMID: 34625994. 6: Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Flinn IW, Kamdar M, Munir T, Walewska R, Corbett G, Fogliatto LM, Herishanu Y, Banerji V, Coutre S, Follows G, Walker P, Karlsson K, Ghia P, Janssens A, Cymbalista F, Woyach JA, Salles G, Wierda WG, Izumi R, Munugalavadla V, Patel P, Wang MH, Wong S, Byrd JC. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020 Apr 18;395(10232):1278-1291. doi: 10.1016/S0140-6736(20)30262-2. Erratum in: Lancet. 2020 May 30;395(10238):1694. PMID: 32305093; PMCID: PMC8151619. 7: Byrd JC, Woyach JA, Furman RR, Martin P, O'Brien S, Brown JR, Stephens DM, Barrientos JC, Devereux S, Hillmen P, Pagel JM, Hamdy A, Izumi R, Patel P, Wang MH, Jain N, Wierda WG. Acalabrutinib in treatment-naive chronic lymphocytic leukemia. Blood. 2021 Jun 17;137(24):3327-3338. doi: 10.1182/blood.2020009617. PMID: 33786588; PMCID: PMC8670015. 8: Roskoski R Jr. Properties of FDA-approved small molecule protein kinase inhibitors: A 2022 update. Pharmacol Res. 2022 Jan;175:106037. doi: 10.1016/j.phrs.2021.106037. Epub 2021 Dec 15. PMID: 34921994. 9: Ahn IE, Brown JR. Targeting Bruton's Tyrosine Kinase in CLL. Front Immunol. 2021 Jun 23;12:687458. doi: 10.3389/fimmu.2021.687458. PMID: 34248972; PMCID: PMC8261291. 10: Estupiñán HY, Berglöf A, Zain R, Smith CIE. Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects. Front Cell Dev Biol. 2021 Mar 11;9:630942. doi: 10.3389/fcell.2021.630942. PMID: 33777941; PMCID: PMC7991787. 11: Jain P, Wang M. Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management. Am J Hematol. 2019 Jun;94(6):710-725. doi: 10.1002/ajh.25487. Epub 2019 Apr 19. PMID: 30963600. 12: Bond DA, Woyach JA. Targeting BTK in CLL: Beyond Ibrutinib. Curr Hematol Malig Rep. 2019 Jun;14(3):197-205. doi: 10.1007/s11899-019-00512-0. PMID: 31028669. 13: Wang M, Rule S, Zinzani PL, Goy A, Casasnovas O, Smith SD, Damaj G, Doorduijn J, Lamy T, Morschhauser F, Panizo C, Shah B, Davies A, Eek R, Dupuis J, Jacobsen E, Kater AP, Le Gouill S, Oberic L, Robak T, Covey T, Dua R, Hamdy A, Huang X, Izumi R, Patel P, Rothbaum W, Slatter JG, Jurczak W. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018 Feb 17;391(10121):659-667. doi: 10.1016/S0140-6736(17)33108-2. Epub 2017 Dec 11. PMID: 29241979; PMCID: PMC7864374. 14: Christensen BW, Zaha VG, Awan FT. Cardiotoxicity of BTK inhibitors: ibrutinib and beyond. Expert Rev Hematol. 2022 Apr;15(4):321-331. doi: 10.1080/17474086.2022.2067526. Epub 2022 Apr 22. PMID: 35437106. 15: Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Flinn IW, Kamdar M, Munir T, Walewska R, Corbett G, Fogliatto LM, Herishanu Y, Banerji V, Coutre S, Follows G, Walker P, Karlsson K, Ghia P, Janssens A, Cymbalista F, Woyach JA, Ferrant E, Wierda WG, Munugalavadla V, Yu T, Wang MH, Byrd JC. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment- naïve chronic lymphocytic leukemia. Leukemia. 2022 Apr;36(4):1171-1175. doi: 10.1038/s41375-021-01485-x. Epub 2022 Jan 1. PMID: 34974526; PMCID: PMC8979808. 16: Wu J, Liu C, Tsui ST, Liu D. Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol. 2016 Sep 2;9(1):80. doi: 10.1186/s13045-016-0313-y. PMID: 27590878; PMCID: PMC5010774. 17: Jain P, Wang ML. Mantle cell lymphoma in 2022-A comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments. Am J Hematol. 2022 May;97(5):638-656. doi: 10.1002/ajh.26523. PMID: 35266562. 18: Bhat SA, Gambril J, Azali L, Chen ST, Rosen L, Palettas M, Wiczer TE, Kalathoor S, Zhao Q, Rogers KA, Kittai A, Grever M, Awan F, Ruz P, Byrd JC, Woyach J, Addison D. Ventricular arrhythmias and sudden death events following acalabrutinib initiation. Blood. 2022 Nov 17;140(20):2142-2145. doi: 10.1182/blood.2022016953. PMID: 35917449. 19: Desikan SP, Venugopal S, Ferrajoli A. BTK inhibitor selection for chronic lymphocytic leukemia: which drug for which patient? Expert Rev Hematol. 2022 May;15(5):403-409. doi: 10.1080/17474086.2022.2074393. Epub 2022 May 11. PMID: 35507054. 20: Castillo JJ, Treon SP. Management of Waldenström macroglobulinemia in 2020. Hematology Am Soc Hematol Educ Program. 2020 Dec 4;2020(1):372-379. doi: 10.1182/hematology.2020000121. 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