Branebrutinib
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MedKoo CAT#: 206954

CAS#: 1912445-55-6

Description: Branebrutinib, also known as BMS-986195, is a potent, covalent, irreversible inhibitor of Bruton’s tyrosine kinase (BTK), a member of the Tec family of non-receptor tyrosine kinases essential in antigen-dependent B-cell signaling and function. BMS-986195 is more than 5000-fold selective for BTK over all kinases outside of the Tec family, and selectivity ranges from 9- to 1010-fold within the Tec family. BMS-986195 inactivated BTK in human whole blood with a rapid rate of inactivation (3.5×10-4 nM-1·min-1) and potently inhibited antigen-dependent interleukin-6 production, CD86 expression and proliferation in B cells (IC50 <1 nM) without effect on antigen-independent measures in the same cells.

Chemical Structure

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Branebrutinib
CAS# 1912445-55-6
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 206954
Name: Branebrutinib
CAS#: 1912445-55-6
Chemical Formula: C20H23FN4O2
Exact Mass: 370.18
Molecular Weight: 370.428
Elemental Analysis: C, 64.85; H, 6.26; F, 5.13; N, 15.13; O, 8.64

Price and Availability

Size Price Availability Quantity
10mg USD 150 Ready to ship
25mg USD 250 Ready to ship
50mg USD 450 Ready to ship
100mg USD 750 Ready to ship
200mg USD 1350 Ready to ship
500mg USD 2950 Ready to ship
1g USD 4250 Ready to ship
2g USD 6650 Ready to ship
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Synonym: BMS-986195; BMS986195; BMS986195; Branebrutinib,

IUPAC/Chemical Name: (S)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

InChi Key: VJPPLCNBDLZIFG-ZDUSSCGKSA-N

InChi Code: InChI=1S/C20H23FN4O2/c1-4-6-16(26)24-13-7-5-8-25(10-13)19-15(21)9-14(20(22)27)18-17(19)11(2)12(3)23-18/h9,13,23H,5,7-8,10H2,1-3H3,(H2,22,27)(H,24,26)/t13-/m0/s1

SMILES Code: O=C(C1=CC(F)=C(N2C[C@@H](NC(C#CC)=O)CCC2)C3=C1NC(C)=C3C)N

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

More Info: Bruton’s tyrosine kinase (BTK) is an attractive, novel therapeutic target for autoimmune disease, as it is required for signal transduction and activation via B-cell receptor, Fc receptor and RANKL pathways.

Biological target: Branebrutinib (BMS-986195) is a covalent, irreversible inhibitor of Bruton’s tyrosine kinase (BTK), with an IC50 of 0.1 nM.
In vitro activity: In B cells stimulated through the B cell receptor (BCR), 5a (Branebrutinib) potently inhibited signaling and functional end points, including calcium flux (IC50 = 7 nM), production of cytokines, proliferation, and surface expression of the costimulatory molecule CD86 (IC50 values of <1 nM). As expected, CD69 expression in peripheral B cells, when stimulated through CD40, was not impacted by 5a since this pathway is not dependent on the kinase activity of BTK to mediate downstream signaling, thus demonstrating the compound’s functional selectivity. When evaluated against IgG-containing immune complex low affinity activating Fcγ (FcγRIIa and FcγRIII) receptor end points in peripheral blood mononuclear cells (PBMC), 5a was highly effective at inhibiting TNFα production with equivalent potency to those measured for the BCR-dependent end points in B cells. In human whole blood assays, 5a potently inhibited BCR-stimulated expression of CD69 on B cells with an IC50 of 11 nM. Reference: J Med Chem. 2019 Apr 11;62(7):3228-3250. https://pubmed.ncbi.nlm.nih.gov/30893553/
In vivo activity: Microcomputed tomography of the hind limbs (Figure 14C) illustrated that 5a provided a dose-dependent protection against pitting, loss of bone mass, woven porous bone, and fusion of the small bones evident in the mice receiving only vehicle. The animals receiving 0.5 mg/kg showed essentially complete protection, as illustrated by the presence of a smooth bone surface and easily recognizable small individual bones of the foot and ankle. The compound was also effective at 0.5 mg/kg po, q.d. in blocking disease progression when dosed in a pseudoestablished dosing mode (data not shown). Reference: J Med Chem. 2019 Apr 11;62(7):3228-3250. https://pubmed.ncbi.nlm.nih.gov/30893553/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 87.0 234.86
Ethanol 38.0 102.58

Preparing Stock Solutions

The following data is based on the product molecular weight 370.43 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. Watterson SH, Liu Q, Beaudoin Bertrand M, Batt DG, Li L, Pattoli MA, Skala S, Cheng L, Obermeier MT, Moore R, Yang Z, Vickery R, Elzinga PA, Discenza L, D'Arienzo C, Gillooly KM, Taylor TL, Pulicicchio C, Zhang Y, Heimrich E, McIntyre KW, Ruan Q, Westhouse RA, Catlett IM, Zheng N, Chaudhry C, Dai J, Galella MA, Tebben AJ, Pokross M, Li J, Zhao R, Smith D, Rampulla R, Allentoff A, Wallace MA, Mathur A, Salter-Cid L, Macor JE, Carter PH, Fura A, Burke JR, Tino JA. Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton's Tyrosine Kinase (BTK). J Med Chem. 2019 Apr 11;62(7):3228-3250. doi: 10.1021/acs.jmedchem.9b00167. Epub 2019 Mar 29. PMID: 30893553.
In vitro protocol: 1. Watterson SH, Liu Q, Beaudoin Bertrand M, Batt DG, Li L, Pattoli MA, Skala S, Cheng L, Obermeier MT, Moore R, Yang Z, Vickery R, Elzinga PA, Discenza L, D'Arienzo C, Gillooly KM, Taylor TL, Pulicicchio C, Zhang Y, Heimrich E, McIntyre KW, Ruan Q, Westhouse RA, Catlett IM, Zheng N, Chaudhry C, Dai J, Galella MA, Tebben AJ, Pokross M, Li J, Zhao R, Smith D, Rampulla R, Allentoff A, Wallace MA, Mathur A, Salter-Cid L, Macor JE, Carter PH, Fura A, Burke JR, Tino JA. Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton's Tyrosine Kinase (BTK). J Med Chem. 2019 Apr 11;62(7):3228-3250. doi: 10.1021/acs.jmedchem.9b00167. Epub 2019 Mar 29. PMID: 30893553.
In vivo protocol: 1. Watterson SH, Liu Q, Beaudoin Bertrand M, Batt DG, Li L, Pattoli MA, Skala S, Cheng L, Obermeier MT, Moore R, Yang Z, Vickery R, Elzinga PA, Discenza L, D'Arienzo C, Gillooly KM, Taylor TL, Pulicicchio C, Zhang Y, Heimrich E, McIntyre KW, Ruan Q, Westhouse RA, Catlett IM, Zheng N, Chaudhry C, Dai J, Galella MA, Tebben AJ, Pokross M, Li J, Zhao R, Smith D, Rampulla R, Allentoff A, Wallace MA, Mathur A, Salter-Cid L, Macor JE, Carter PH, Fura A, Burke JR, Tino JA. Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton's Tyrosine Kinase (BTK). J Med Chem. 2019 Apr 11;62(7):3228-3250. doi: 10.1021/acs.jmedchem.9b00167. Epub 2019 Mar 29. PMID: 30893553.

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1: von Hundelshausen P, Siess W. Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease. Cancers (Basel). 2021 Mar 4;13(5):1103. doi: 10.3390/cancers13051103. PMID: 33806595; PMCID: PMC7961939.


2: Wu CP, Murakami M, Wu YS, Chi YC, Hsiao SH, Huang YH, Hung TH, Ambudkar SV. Branebrutinib (BMS-986195), a Bruton's Tyrosine Kinase Inhibitor, Resensitizes P-Glycoprotein-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Agents. Front Cell Dev Biol. 2021 Jul 19;9:699571. doi: 10.3389/fcell.2021.699571. PMID: 34350184; PMCID: PMC8326665.


3: Catlett IM, Nowak M, Kundu S, Zheng N, Liu A, He B, Girgis IG, Grasela DM. Safety, pharmacokinetics and pharmacodynamics of branebrutinib (BMS-986195), a covalent, irreversible inhibitor of Bruton's tyrosine kinase: Randomised phase I, placebo-controlled trial in healthy participants. Br J Clin Pharmacol. 2020 Sep;86(9):1849-1859. doi: 10.1111/bcp.14290. Epub 2020 Apr 12. PMID: 32198939; PMCID: PMC7444767.


4: Watterson SH, Liu Q, Beaudoin Bertrand M, Batt DG, Li L, Pattoli MA, Skala S, Cheng L, Obermeier MT, Moore R, Yang Z, Vickery R, Elzinga PA, Discenza L, D'Arienzo C, Gillooly KM, Taylor TL, Pulicicchio C, Zhang Y, Heimrich E, McIntyre KW, Ruan Q, Westhouse RA, Catlett IM, Zheng N, Chaudhry C, Dai J, Galella MA, Tebben AJ, Pokross M, Li J, Zhao R, Smith D, Rampulla R, Allentoff A, Wallace MA, Mathur A, Salter-Cid L, Macor JE, Carter PH, Fura A, Burke JR, Tino JA. Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton's Tyrosine Kinase (BTK). J Med Chem. 2019 Apr 11;62(7):3228-3250. doi: 10.1021/acs.jmedchem.9b00167. Epub 2019 Mar 29. PMID: 30893553.


5: Zheng N, Catlett IM, Taylor K, Gu H, Pattoli MA, Neely RJ, Li W, Allentoff A, Yuan X, Ciccimaro E, Yao M, Warrack BM, Burke JR, Zhang YJ, Pillutla R, Zeng J. Determination of Real Time in Vivo Drug Receptor Occupancy for a Covalent Binding Drug as a Clinical Pharmacodynamic Biomarker by Immunocapture-LC-MS/MS. Anal Chem. 2019 Jul 2;91(13):8443-8452. doi: 10.1021/acs.analchem.9b01462. Epub 2019 Jun 19. PMID: 31247719.


6: Dolgin E. BTK blockers make headway in multiple sclerosis. Nat Biotechnol. 2021 Jan;39(1):3-5. doi: 10.1038/s41587-020-00790-7. PMID: 33432223.


7: Yang Z. Achieving a low human dose for targeted covalent drugs: Pharmacokinetic and pharmacodynamic considerations on target characteristics and drug attributes. Biopharm Drug Dispos. 2021 Apr;42(4):150-159. doi: 10.1002/bdd.2263. Epub 2021 Apr 2. PMID: 33547681.