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MedKoo Cat#: 465403 | Name: Pirtobrutinib
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Description:

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

Pirtobrutinib, also known as LOXO-305 and LY 3527727, is a Bruton's tyrosine kinase (BTK) inhibitor and antineoplastic agent. Pirtobrutinib showed promising initial efficacy in pts with pretreated Richter transformation with extremely poor prognosis, including in patients who had received prior chemoimmunotherapy and covalent BTK inhibitors. Pirtobrutinib is a highly selective and potent non-covalent BTK inhibitor (BTKi) with high oral bioavailability and a long half-life, resulting in robust BTK target coverage even in high-grade malignancies with high BTK protein turnover.

Chemical Structure

Pirtobrutinib
Pirtobrutinib
CAS#2101700-15-4 (S-isomer)

Theoretical Analysis

MedKoo Cat#: 465403

Name: Pirtobrutinib

CAS#: 2101700-15-4 (S-isomer)

Chemical Formula: C22H21F4N5O3

Exact Mass: 479.1581

Molecular Weight: 479.44

Elemental Analysis: C, 55.12; H, 4.42; F, 15.85; N, 14.61; O, 10.01

Price and Availability

Size Price Availability Quantity
25mg USD 150.00 Ready to ship
50mg USD 250.00 Ready to ship
100mg USD 450.00 Ready to ship
200mg USD 750.00 Ready to ship
500mg USD 1,450.00 Ready to ship
1g USD 2,250.00 Ready to ship
2g USD 3,950.00 Ready to ship
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Related CAS #
2101700-15-4 (S-isomer) 2101700-14-3 (R-isomer)
Synonym
Pirtobrutinib; LOXO-305; LOXO 305; LOXO305; LY 3527727; LY-3527727; LY3527727;
IUPAC/Chemical Name
(S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide
InChi Key
FWZAWAUZXYCBKZ-NSHDSACASA-N
InChi Code
InChI=1S/C22H21F4N5O3/c1-11(22(24,25)26)31-19(27)17(20(28)32)18(30-31)13-5-3-12(4-6-13)10-29-21(33)15-9-14(23)7-8-16(15)34-2/h3-9,11H,10,27H2,1-2H3,(H2,28,32)(H,29,33)/t11-/m0/s1
SMILES Code
O=C(C1=C(N)N([C@@H](C)C(F)(F)F)N=C1C2=CC=C(CNC(C3=CC(F)=CC=C3OC)=O)C=C2)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
To be determined
Shelf Life
>2 years if stored properly
Drug Formulation
To be determined
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
Pirtobrutinib is a highly potent and selective non-covalent BTK inhibitor currently being tested in B-cell malignancies. It comprises nanomolar potency against wild-type and C481-mutant BTK in cell and enzyme assays, with greater than 300-fold selectivity for BTK vs 370 other kinases. Because of reversible binding mode, BTK inhibition is not impacted by an intrinsic rate of BTK turnover, and its favorable pharmacologic properties allow for sustained BTK inhibition throughout the dosing interval.
Biological target:
Pirtobrutinib (LOXO-305), a highly selective and non-covalent next generation BTK inhibitor, inhibits diverse BTK C481 substitution mutations.
In vitro activity:
LOXO-305 potently inhibits Y223 autophosphorylation of all active BTK mutants (BTK C481S, C481T, and C481R). In vitro studies showed that LOXO-305 potently led to inhibition of BCR signaling and cell survival in both treatment-naive and BTK C481 mutant CLL primary cells, indicating that LOXO-305 could be used for treating treatment-naïve and ibrutinib-resistant CLL patients [60–62]. In high proliferating tumors, high rates of BTK turnover may result in incomplete target inhibition by covalent inhibitors, which ultimately lead to resistance to these covalent BTK inhibitors. LOXO-305 achieves remarkable target coverage even in the presence of high rates of BTK turnover, providing a rationale for using LOXO-305 in aggressive B cell lymphomas including DLBCL. Reference: J Hematol Oncol. 2021; 14: 40. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937220/
In vivo activity:
TBD
Solvent mg/mL mM comments
Solubility
DMSO 50.0 104.29
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 479.44 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. Gu D, Tang H, Wu J, Li J, Miao Y. Targeting Bruton tyrosine kinase using non-covalent inhibitors in B cell malignancies. J Hematol Oncol. 2021 Mar 6;14(1):40. doi: 10.1186/s13045-021-01049-7. PMID: 33676527; PMCID: PMC7937220.
In vitro protocol:
1. Gu D, Tang H, Wu J, Li J, Miao Y. Targeting Bruton tyrosine kinase using non-covalent inhibitors in B cell malignancies. J Hematol Oncol. 2021 Mar 6;14(1):40. doi: 10.1186/s13045-021-01049-7. PMID: 33676527; PMCID: PMC7937220.
In vivo protocol:
TBD
1: Dasanu CA, Mann SK, Baidya M, Mdluli XP, Stapleton AE, Codreanu I. Evaluation of infectious morbidity due to BTK inhibitors in indolent B-cell lymphomas: latest research findings and systematic analysis. Expert Opin Pharmacother. 2024 Aug 13:1-16. doi: 10.1080/14656566.2024.2390121. Epub ahead of print. PMID: 39109526. 2: Wang JF, Wang Y. Evaluating pirtobrutinib for the treatment of relapsed or refractory mantle cell lymphoma. Expert Rev Hematol. 2024 Aug 8:1-9. doi: 10.1080/17474086.2024.2389993. Epub ahead of print. PMID: 39109468. 3: Mehra S, Nicholls M, Taylor J. The Evolving Role of Bruton's Tyrosine Kinase Inhibitors in B Cell Lymphomas. Int J Mol Sci. 2024 Jul 9;25(14):7516. doi: 10.3390/ijms25147516. PMID: 39062757; PMCID: PMC11276629. 4: Lawlor K. Comment: Pirtobrutinib: A New and Distinctive Treatment Option for B-Cell Malignancies. Ann Pharmacother. 2024 Sep;58(9):978. doi: 10.1177/10600280241258777. Epub 2024 Jul 23. PMID: 39044373. 5: Schultze MD, Reeves DJ. Reply: Pirtobrutinib: A New and Distinctive Treatment Option for B-Cell Malignancies. Ann Pharmacother. 2024 Sep;58(9):979. doi: 10.1177/10600280241258779. Epub 2024 Jul 23. PMID: 39044370. 6: Tadmor T. Overcoming the unmet need of Richter transformation: the use of pirtobrutinib. Lancet Haematol. 2024 Sep;11(9):e636-e637. doi: 10.1016/S2352-3026(24)00204-7. Epub 2024 Jul 18. PMID: 39033771. 7: Wierda WG, Shah NN, Cheah CY, Lewis D, Hoffmann MS, Coombs CC, Lamanna N, Ma S, Jagadeesh D, Munir T, Wang Y, Eyre TA, Rhodes JM, McKinney M, Lech-Maranda E, Tam CS, Jurczak W, Izutsu K, Alencar AJ, Patel MR, Seymour JF, Woyach JA, Thompson PA, Abada PB, Ho C, McNeely SC, Marella N, Nguyen B, Wang C, Ruppert AS, Nair B, Liu H, Tsai DE, Roeker LE, Ghia P. Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in patients with B-cell malignancies: analysis of the Richter transformation subgroup from the multicentre, open-label, phase 1/2 BRUIN study. Lancet Haematol. 2024 Sep;11(9):e682-e692. doi: 10.1016/S2352-3026(24)00172-8. Epub 2024 Jul 18. PMID: 39033770. 8: Cool A, Nong T, Montoya S, Taylor J. BTK inhibitors: past, present, and future. Trends Pharmacol Sci. 2024 Aug;45(8):691-707. doi: 10.1016/j.tips.2024.06.006. Epub 2024 Jul 17. PMID: 39025681. 9: Kong C, Wu M, Lu Q, Ke B, Xie J, Li A. PI3K/AKT confers intrinsic and acquired resistance to pirtobrutinib in chronic lymphocytic leukemia. Leuk Res. 2024 Jul 7;144:107548. doi: 10.1016/j.leukres.2024.107548. Epub ahead of print. PMID: 39018782. 10: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–. Pirtobrutinib. 2024 Jul 15. PMID: 39110822. 11: Matsumura N, Mandai M. PMDA regulatory update on approval and revision of the precautions for use of anticancer drugs: approval selpercatinib for solid tumor with RET fusion, gumarontinib for non-small cell lung cancer with MET gene exon 14 skipping mutation, momelotinib for myelofibrosis, bexarotene for adult T-cell leukemia/lymphoma, valemetostat for peripheral T-cell lymphoma, and pirtobrutinib for mantle cell lymphoma in Japan. Int J Clin Oncol. 2024 Sep;29(9):1207-1208. doi: 10.1007/s10147-024-02579-z. PMID: 39007945. 12: Kriegelstein M, Hojcsková J, Hroch M, Marek A. Direct Multi-Deuterium Labelling of Pirtobrutinib. J Labelled Comp Radiopharm. 2024 Jul;67(9):314-323. doi: 10.1002/jlcr.4117. Epub 2024 Jul 14. PMID: 39004786. 13: Stożek-Tutro A, Reczek M, Kawalec P. Safety profile of first-line targeted therapies in elderly and/or comorbid chronic lymphocytic leukaemia patients (unfit subpopulation). A systematic review and network meta-analysis. Crit Rev Oncol Hematol. 2024 Sep;201:104428. doi: 10.1016/j.critrevonc.2024.104428. Epub 2024 Jul 3. PMID: 38969250. 14: Aslan B, Manyam G, Iles LR, Tantawy SI, Desikan SP, Wierda WG, Gandhi V. Transcriptomic and proteomic differences in BTK-WT and BTK-mutated CLL and their changes during therapy with pirtobrutinib. Blood Adv. 2024 Jul 5:bloodadvances.2023012360. doi: 10.1182/bloodadvances.2023012360. Epub ahead of print. PMID: 38968154. 15: Roeker LE, Woyach JA, Cheah CY, Coombs CC, Shah NN, Wierda WG, Patel MR, Lamanna N, Tsai DE, Nair BC, Wang C, Zhao X, Liu D, Radtke D, Chapman S, Marella N, McNeely SC, Brown JR. Fixed-Duration Pirtobrutinib plus Venetoclax with or without Rituximab in Relapsed/Refractory CLL: Phase 1b BRUIN Trial. Blood. 2024 Jun 11:blood.2024024510. doi: 10.1182/blood.2024024510. Epub ahead of print. PMID: 38861666. 16: Cheson BD, Sharman JP. Current Approaches and Novel New Agents in the Treatment of Chronic Lymphocytic Leukemia. JCO Oncol Pract. 2024 Jun 7:OP2300770. doi: 10.1200/OP.23.00770. Epub ahead of print. PMID: 38848511. 17: Fatima SK, Khan S, Mughal ZUN, Rangwala HS, Rangwala BS, Siddiq MA, Ali M, Farah AA. Pirtobrutinib: a promising therapy for overcoming the resistance of ibrutinib in mantle cell lymphoma. Ann Med Surg (Lond). 2024 Apr 15;86(6):3189-3191. doi: 10.1097/MS9.0000000000002045. PMID: 38846878; PMCID: PMC11152862. 18: Roeker LE, Coombs CC, Shah NN, Jurczak W, Woyach JA, Cheah CY, Patel K, Maddocks K, Wang Y, Zinzani PL, Munir T, Koh Y, Thompson MC, Muehlenbein CE, Wang C, Sizelove R, Abhyankar S, Hasanabba S, Tsai DE, Eyre TA, Wang M. Safety of Extended Pirtobrutinib Exposure in Relapsed and/or Refractory B-Cell Malignancies. Acta Haematol. 2024 Jun 5:1-17. doi: 10.1159/000539587. Epub ahead of print. PMID: 38824917. 19: Woyach JA. Pirtobrutinib in relapsed or refractory CLL and SLL. Clin Adv Hematol Oncol. 2024 Jun;22(5):230-231. PMID: 38805315. 20: Wiśniewski K, Puła B. A Review of Resistance Mechanisms to Bruton's Kinase Inhibitors in Chronic Lymphocytic Leukemia. Int J Mol Sci. 2024 May 11;25(10):5246. doi: 10.3390/ijms25105246. PMID: 38791284; PMCID: PMC11120758.