Spebrutinib
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MedKoo CAT#: 204480

CAS#: 1202757-89-8

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

Theoretical Analysis

MedKoo Cat#: 204480
Name: Spebrutinib
CAS#: 1202757-89-8
Chemical Formula: C22H22FN5O3
Exact Mass: 423.17067
Molecular Weight: 423.44
Elemental Analysis: C, 62.40; H, 5.24; F, 4.49; N, 16.54; O, 11.34

Price and Availability

Size Price Availability Quantity
25.0mg USD 90.0 Ready to ship
50.0mg USD 150.0 Ready to ship
100.0mg USD 250.0 Ready to ship
200.0mg USD 450.0 Ready to ship
500.0mg USD 850.0 Ready to ship
1.0g USD 1450.0 Ready to ship
2.0g USD 2450.0 Ready to ship
5.0g USD 4650.0 Ready to ship
10.0g USD 6750.0 Ready to ship
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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

Biological target: Spebrutinib (CC-292) is a covalent inhibitor of Btk with IC50 value of 0.5 nM.
In vitro activity: CC-292 (10–1000 nM) had a cytostatic effect in a subset of cell lines, with REC-1, MINO and UPN-1 appearing to be the most sensitive, while MAVER-1 and Z138 were the most resistant to CC-292, following a trend similar to that for ibrutinib (Figure 1A,B). CC-292 induced marginal apoptosis (10–15%) in the most sensitive cell lines (UPN-1 and REC-1) (Online Supplementary Figure S1). Identification of Tyr223 pBTK is considered a surrogate marker for kinase activity.6 MCL cell lines pre-incubated with CC-292 were IgM-stimulated to mimic BCR activation. As displayed in Figure 1C, CC-292 significantly reduced both constitutive and IgM-induced BTK phosphorylation at the Y223 residue in MCL cell lines and primary cells, independently of their sensitivity to the inhibitor. Reference: Haematologica. 2017 Nov; 102(11): e447–e451. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664406/
In vivo activity: Mice treated with CC-292 experienced a substantial decrease in the number of both Ly6Chi and Ly6Clow monocytes (p = 0.0016 and p < 0.0002, respectively; Fig. 5b), with no major alteration of the patrolling-to-inflammatory ratio (Fig. 5a). Moreover, this study analyzed the effect of the treatment on T-cell populations in PB, which are known to increase along with disease course. This study detected a decrease in CD4+ and CD8+ T-cell numbers after single-agent treatment (CD8+: p = 0.0128 and CD4+: p = 0.1020). While CLL development is associated with a drop in the CD4+/CD8+ cell ratio due to CD8+ T-cell expansion, CC-292 treatment resulted in a significant increase in the CD4+/CD8+ cell ratio in PB (p = 0.0079; Supporting Information Fig. S6e). Collectively, these data show that CC-292 treatment results in a normalization of CLL-induced changes in monocyte and T-cell numbers. Reference: Int J Cancer. 2019 Jun 1;144(11):2762-2773. https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.32010

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
Ethanol 0.5 1.18
DMSO:PBS (pH 7.2) (1:30) 0.03 0.07
DMF 20.0 47.23

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.



Additional Information

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).