WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 465403
CAS#: 2101700-15-4 (S-isomer)
Description: 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.
MedKoo Cat#: 465403
Name: Pirtobrutinib
CAS#: 2101700-15-4 (S-isomer)
Chemical Formula: C22H21F4N5O3
Exact Mass: 479.1581
Molecular Weight: 479.4356
Elemental Analysis: C, 55.12; H, 4.42; F, 15.85; N, 14.61; O, 10.01
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
| 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 | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 50.0 | 104.29 |
The following data is based on the product molecular weight 479.4356 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. 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: Sarosiek S, Treon SP, Castillo JJ. How to Sequence Therapies in Waldenström Macroglobulinemia. Curr Treat Options Oncol. 2021 Aug 23;22(10):92. doi: 10.1007/s11864-021-00890-9. PMID: 34426943.
2: BTK Inhibitor May Treat Drug-Resistant CLL, SLL. Cancer Discov. 2021 May;11(5):998. doi: 10.1158/2159-8290.CD-NB2021-0327. Epub 2021 Mar 26. PMID: 33771769.
3: Romero D. Initial pirtobrutinib data show promise. Nat Rev Clin Oncol. 2021 May;18(5):258. doi: 10.1038/s41571-021-00505-0. PMID: 33758377.
4: Mato AR, Shah NN, Jurczak W, Cheah CY, Pagel JM, Woyach JA, Fakhri B, Eyre TA, Lamanna N, Patel MR, Alencar A, Lech-Maranda E, Wierda WG, Coombs CC, Gerson JN, Ghia P, Le Gouill S, Lewis DJ, Sundaram S, Cohen JB, Flinn IW, Tam CS, Barve MA, Kuss B, Taylor J, Abdel-Wahab O, Schuster SJ, Palomba ML, Lewis KL, Roeker LE, Davids MS, Tan XN, Fenske TS, Wallin J, Tsai DE, Ku NC, Zhu E, Chen J, Yin M, Nair B, Ebata K, Marella N, Brown JR, Wang M. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021 Mar 6;397(10277):892-901. doi: 10.1016/S0140-6736(21)00224-5. PMID: 33676628.
5: Michot JM, Ribrag V. Pirtobrutinib shows evidence to inaugurate a third generation of BTK inhibitors. Lancet. 2021 Mar 6;397(10277):855-857. doi: 10.1016/S0140-6736(21)00235-X. PMID: 33676615.
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.
