Spebrutinib
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MedKoo CAT#: 204480

CAS#: 1202757-89-8 (free base)

Description: Spebrutinib, also known as AVL-292 or CC-292, is an orally bioavailable, selective inhibitor of BrutonÂ’s agammaglobulinemia tyrosine kinase (BTK), with potential antineoplastic activity. Upon administration, AVL-292 targets and covalently binds to BTK, thereby preventing its activity. By irreversibly inhibiting BTK, administration of this agent may lead to an inhibition of B cell receptor (BCR) signaling and may inhibit cell proliferation of B-cell malignancies.


Chemical Structure

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Spebrutinib
CAS# 1202757-89-8 (free base)

Theoretical Analysis

MedKoo Cat#: 204480
Name: Spebrutinib
CAS#: 1202757-89-8 (free base)
Chemical Formula: C22H22FN5O3
Exact Mass: 423.17
Molecular Weight: 423.440
Elemental Analysis: C, 62.40; H, 5.24; F, 4.49; N, 16.54; O, 11.34

Price and Availability

Size Price Availability Quantity
25mg USD 90 Ready to ship
50mg USD 150 Ready to ship
100mg USD 250 Ready to ship
200mg USD 450 Ready to ship
500mg USD 850 Ready to ship
1g USD 1450 Ready to ship
2g USD 2450 Ready to ship
5g USD 4650 Ready to ship
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Related CAS #: 1360053-81-1 (besylate)   1202757-89-8 (free base)  

Synonym: CC292; CC-292; CC 292; AVL292; AVL-292; AVL 292; Spebrutinib.

IUPAC/Chemical Name: N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide

InChi Key: KXBDTLQSDKGAEB-UHFFFAOYSA-N

InChi Code: InChI=1S/C22H22FN5O3/c1-3-20(29)25-16-5-4-6-17(13-16)26-21-19(23)14-24-22(28-21)27-15-7-9-18(10-8-15)31-12-11-30-2/h3-10,13-14H,1,11-12H2,2H3,(H,25,29)(H2,24,26,27,28)

SMILES Code: C=CC(NC1=CC=CC(NC2=NC(NC3=CC=C(OCCOC)C=C3)=NC=C2F)=C1)=O

Appearance: 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: AVL-292 has demonstrated efficacy in animal models of rheumatoid arthritis and multiple sclerosis, diseases in which B cells play an important role. Btk plays a critical role in the development and activation of B cells, and its inhibition will be of therapeutic significance in the treatment of both of B cell-related hematological cancers (e.g. non-Hodgkin lymphoma (NHL) and B cell chronic lymphocytic leukemia (B-CLL), and autoimmune diseases (e.g. rheumatoid arthritis). (source: http://www.avilatx.com/pipeline/bruton%27s-tyrosine-kinase-inhibitor-program.html).      

Biological target: Spebrutinib is a covalent inhibitor of Btk with IC50 value of 0.5 nM.
In vitro activity: Spebrutinib showed a cytostatic effect in a subset of cell lines, with REC-1, MINO, and UPN-1 being the most sensitive, while MAVER-1 and Z138 were the most resistant to spebrutinib, similar to ibrutinib. Marginal apoptosis (10–15%) was observed in the most sensitive cell lines (UPN-1 and REC-1). Spebrutinib reduced both constitutive and IgM-induced BTK phosphorylation at the Y223 residue in MCL cell lines and primary cells, regardless of their sensitivity to the inhibitor. Reference: Haematologica. 2017 Nov; 102(11): e447–e451. https://pubmed.ncbi.nlm.nih.gov/28838994/
In vivo activity: Spebrutinib is a specific BTK inhibitor with promising performance in combination with bendamustine in chronic lymphocytic leukemia (CLL). In a mouse model of CLL, spebrutinib reduced tumor load and normalized tumor-associated expansion of T cells and monocytes, while not affecting T cell function. The combination of spebrutinib and bendamustine impaired CLL cell proliferation in vivo and enhanced the control of CLL progression. Reference: Int J Cancer. 2019 Jun 1;144(11):2762-2773. https://pubmed.ncbi.nlm.nih.gov/30468254/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
Ethanol 0.5 1.18
DMSO:PBS (pH 7.2) (1:30) 0.0 0.07
Ethanol 0.5 1.18

Preparing Stock Solutions

The following data is based on the product molecular weight 423.44 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. Vidal-Crespo A, Rodriguez V, Matas-Cespedes A, Lee E, Rivas-Delgado A, Giné E, Navarro A, Beà S, Campo E, López-Guillermo A, Lopez-Guerra M, Roué G, Colomer D, Pérez-Galán P. The Bruton tyrosine kinase inhibitor CC-292 shows activity in mantle cell lymphoma and synergizes with lenalidomide and NIK inhibitors depending on nuclear factor-κB mutational status. Haematologica. 2017 Nov;102(11):e447-e451. doi: 10.3324/haematol.2017.168930. Epub 2017 Aug 24. PMID: 28838994; PMCID: PMC5664406. 2. Arnason JE, Brown JR. B cell receptor pathway in chronic lymphocytic leukemia: specific role of CC-292. Immunotargets Ther. 2014 Jan 24;3:29-38. doi: 10.2147/ITT.S37419. PMID: 27471698; PMCID: PMC4918232. 3. Lee-Vergés E, Hanna BS, Yazdanparast H, Rodríguez V, Rodríguez ML, Giró A, Vidal-Crespo A, Rosich L, Amador V, Aymerich M, Villamor N, Delgado J, Lichter P, Pérez-Galán P, López-Guerra M, Campo E, Seiffert M, Colomer D. Selective BTK inhibition improves bendamustine therapy response and normalizes immune effector functions in chronic lymphocytic leukemia. Int J Cancer. 2019 Jun 1;144(11):2762-2773. doi: 10.1002/ijc.32010. Epub 2019 Jan 16. PMID: 30468254. 4. Daryaee F, Zhang Z, Gogarty KR, Li Y, Merino J, Fisher SL, Tonge PJ. A quantitative mechanistic PK/PD model directly connects Btk target engagement and in vivo efficacy. Chem Sci. 2017 May 1;8(5):3434-3443. doi: 10.1039/c6sc03306g. Epub 2017 Mar 14. PMID: 28507715; PMCID: PMC5417014.
In vitro protocol: 1. Vidal-Crespo A, Rodriguez V, Matas-Cespedes A, Lee E, Rivas-Delgado A, Giné E, Navarro A, Beà S, Campo E, López-Guillermo A, Lopez-Guerra M, Roué G, Colomer D, Pérez-Galán P. The Bruton tyrosine kinase inhibitor CC-292 shows activity in mantle cell lymphoma and synergizes with lenalidomide and NIK inhibitors depending on nuclear factor-κB mutational status. Haematologica. 2017 Nov;102(11):e447-e451. doi: 10.3324/haematol.2017.168930. Epub 2017 Aug 24. PMID: 28838994; PMCID: PMC5664406. 2. Arnason JE, Brown JR. B cell receptor pathway in chronic lymphocytic leukemia: specific role of CC-292. Immunotargets Ther. 2014 Jan 24;3:29-38. doi: 10.2147/ITT.S37419. PMID: 27471698; PMCID: PMC4918232.
In vivo protocol: 1. Lee-Vergés E, Hanna BS, Yazdanparast H, Rodríguez V, Rodríguez ML, Giró A, Vidal-Crespo A, Rosich L, Amador V, Aymerich M, Villamor N, Delgado J, Lichter P, Pérez-Galán P, López-Guerra M, Campo E, Seiffert M, Colomer D. Selective BTK inhibition improves bendamustine therapy response and normalizes immune effector functions in chronic lymphocytic leukemia. Int J Cancer. 2019 Jun 1;144(11):2762-2773. doi: 10.1002/ijc.32010. Epub 2019 Jan 16. PMID: 30468254. 2. Daryaee F, Zhang Z, Gogarty KR, Li Y, Merino J, Fisher SL, Tonge PJ. A quantitative mechanistic PK/PD model directly connects Btk target engagement and in vivo efficacy. Chem Sci. 2017 May 1;8(5):3434-3443. doi: 10.1039/c6sc03306g. Epub 2017 Mar 14. PMID: 28507715; PMCID: PMC5417014.

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1: Burger JA. Bruton's tyrosine kinase (BTK) inhibitors in clinical trials. Curr Hematol Malig Rep. 2014 Mar;9(1):44-9. doi: 10.1007/s11899-013-0188-8. PubMed PMID: 24357428.