Pirtobrutinib
(Synonyms: LOXO-305) 目录号 : GC62515
A BTK inhibitor
Cas No.:2101700-15-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Pirtobrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK).1 It inhibits wild-type and mutant BTK (IC50s = 10-100 and <10 nM for wild-type BTK and BTKC481S, respectively). It is selective for BTK over EGFR (IC50 = 1-10 ?M). Pirtobrutinib decreases the number of Ki67-positive cells, a marker of cell proliferation, in MEC-1 chronic lymphocytic leukemia (CLL) mouse xenograft models using MEC-1 cells that express either wild-type BTK or BTKC481S.2
1.Guisot, N.Compounds useful as kinase inhibitors(2017) 2.Aslan, B., Kismali, G., Iles, L.R., et al.Pirtobrutinib inhibits wild-type and mutant Bruton's tyrosine kinase-mediated signaling in chronic lymphocytic leukemiaBlood Cancer J.12(5)80(2022)
| Cas No. | 2101700-15-4 | SDF | |
| 别名 | LOXO-305 | ||
| 分子式 | C22H21F4N5O3 | 分子量 | 479.43 |
| 溶解度 | DMSO : 50 mg/mL (104.29 mM; Need ultrasonic) | 储存条件 | 4°C, stored under nitrogen |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0858 mL | 10.4291 mL | 20.8581 mL |
| 5 mM | 0.4172 mL | 2.0858 mL | 4.1716 mL |
| 10 mM | 0.2086 mL | 1.0429 mL | 2.0858 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study
Lancet 2021 Mar 6;397(10277):892-901.PMID:33676628DOI:10.1016/S0140-6736(21)00224-5.
Background: Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of Pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients. Methods: Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/2 trial of the BTK inhibitor Pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529. Findings: 323 patients were treated with Pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between Pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with Pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date. Interpretation: Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients. Funding: Loxo Oncology.
Pirtobrutinib inhibits wild-type and mutant Bruton's tyrosine kinase-mediated signaling in chronic lymphocytic leukemia
Blood Cancer J 2022 May 20;12(5):80.PMID:35595730DOI:10.1038/s41408-022-00675-9.
Pirtobrutinib (LOXO-305), a reversible inhibitor of Bruton's tyrosine kinase (BTK), was designed as an alternative strategy to treat ibrutinib-resistant disease that develops due to C481 kinase domain mutations. The clinical activity of Pirtobrutinib has been demonstrated in CLL, but the mechanism of action has not been investigated. We evaluated Pirtobrutinib in 4 model systems: first, MEC-1, a CLL cell line overexpressing BTKWT, BTKC481S, or BTKC481R; second, murine models driven by MEC-1 overexpressing BTKWT or BTKC481S; third, in vitro incubations of primary CLL cells; and finally, CLL patients during Pirtobrutinib therapy (NCT03740529, ClinicalTrials.gov). Pirtobrutinib inhibited BTK activation as well as downstream signaling in MEC-1 isogenic cells overexpressing BTKWT, BTKC481S, or BTKC481R. In mice, overall survival was short due to aggressive disease. Pirtobrutinib treatment for 2 weeks led to reduction of spleen and liver weight in BTKWT and BTKC481S cells, respectively. In vitro incubations of CLL cells harboring wild-type or mutant BTK had inhibition of the BCR pathway with either ibrutinib or Pirtobrutinib treatment. Pirtobrutinib therapy resulted in inhibition of BTK phosphorylation and downstream signaling initially in all cases irrespective of their BTK profile, but these effects started to revert in cases with other BCR pathway mutations such as PLCG2 or PLEKHG5. Levels of CCL3 and CCL4 in plasma were marginally higher in patients with mutated BTK; however, there was a bimodal distribution. Both chemokines were decreased at early time points and mimicked BCR pathway protein changes. Collectively, these results demonstrate that Pirtobrutinib is an effective BTK inhibitor for CLL harboring wild-type or mutant BTK as observed by changes in CCL3 and CCL4 biomarkers and suggest that alterations in BCR pathway signaling are the mechanism for its clinical effects. Long-term evaluation is needed for BTK gatekeeper residue variation along with pathologic kinase substitution or mutations in other proteins in the BCR pathway.
The potential of Pirtobrutinib in multiple B-cell malignancies
Ther Adv Hematol 2022 Jun 16;13:20406207221101697.PMID:35747462DOI:10.1177/20406207221101697.
Bruton's tyrosine kinase (BTK) is a critical downstream signaling element from the B-cell receptor (BCR) that has been effectively inhibited in B-cell cancers by irreversible, covalent inhibitors including ibrutinib and acalabrutinib. All FDA-approved covalent BTK inhibitors rely on binding to the cysteine 481 (C481) amino acid within the active site of BTK, thus rendering it inert. While covalent BTK inhibitors have been very successful in multiple B-cell malignancies, improving both overall survival and progression-free survival relative to chemoimmunotherapy in phase 3 trials, they can be limited by intolerance and disease progression. Pirtobrutinib is a novel, highly selective, and non-covalent BTK inhibitor that binds independently of C481, and in a recent, first-in-human phase 1/2 clinical trial was shown to be extremely well tolerated and lead to remissions in relapsed/refractory patients with multiple B-cell malignancies. Here, we review the pharmacologic rationale for pursuing non-covalent BTK inhibitors, the clinical need for such inhibitors, existing safety, and resistance mechanism data for Pirtobrutinib, and the forthcoming clinical trials that seek to define the clinical utility of Pirtobrutinib, which has the potential to fulfill multiple areas of unmet clinical need for patients with B-cell malignancies.
Pirtobrutinib: First Approval
Drugs 2023 Apr 1.PMID:37004673DOI:10.1007/s40265-023-01860-1.
Pirtobrutinib (JaypircaTM), a highly selective, non-covalent, reversible Bruton's tyrosine kinase (BTK) inhibitor, is being developed by Eli Lilly and Company (Lilly) for the treatment of B-cell leukemias and lymphomas. In January 2023, Pirtobrutinib was approved in the USA under the Accelerated Approval pathway for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. This article summarizes the milestones in the development of Pirtobrutinib leading to this first approval for the treatment of adult patients with relapsed or refractory MCL.
MCL-133 Pirtobrutinib, a Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Previously Treated Mantle Cell Lymphoma: Updated Results From the Phase 1/2 BRUIN Study
Clin Lymphoma Myeloma Leuk 2022 Oct;22 Suppl 2:S394-S395.PMID:36164120DOI:10.1016/S2152-2650(22)01569-5.
Context: Covalent BTK inhibitors (BTKi) have transformed the management of mantle cell lymphoma (MCL), but most patients will require additional treatment. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild-type and C481-mutated BTK with equal low nM potency. Objective: To evaluate Pirtobrutinib safety and efficacy in patients with MCL. Design: BRUIN is an ongoing multicenter phase 1/2 study (NCT03740529) of Pirtobrutinib monotherapy. Setting: Global; community hospitals, academic medical centers. Patients: Patients with advanced B-cell malignancies. Interventions: Oral Pirtobrutinib, phase 1 dose-escalated in a standard 3+3 design, phase 2 continuous therapy, 28-day cycles. Main outcome measures: The primary phase 1 objective was to determine the recommended phase 2 dose (RP2D) and the primary phase 2 objective was overall response rate (ORR); secondary objectives included duration of response, progression-free survival, overall survival, safety/tolerability, and pharmacokinetics. Results: As of 27 September 2020, 323 patients (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other NHL) were treated on 7 dose levels (25-300mg QD). No DLTs were reported and MTD was not reached (n=323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent treatment-emergent adverse events regardless of attribution or grade seen in >10% of patients. The most common adverse event of grade ≥3 was neutropenia (10%). Five (1%) patients discontinued due to treatment-related adverse events. 52 prior BTKi treated MCL patients were efficacy evaluable with an ORR of 52% (95% CI 38-66; 13 CR [25%], 14 PR [27%], 9 SD [17%]), 11 PD [21%] and 5 [10%] discontinued prior to first response assessment). Median follow-up was 6 months (0.7-18.3+). Responses were observed in 9/14 patients (64%) with prior autologous or allogeneic stem cell transplant, and 2/2 with prior CAR-T cell therapy. Conclusions: Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL following multiple prior lines of therapy, including a covalent BTKi. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 60 new patients with MCL and an additional 10 months since the prior data-cut will be presented.