Pilaralisib
(Synonyms: 2-氨基-N-[3-[N-[3-[(2-氯-5-甲氧基苯基)氨基]喹喔啉-2-基]氨基磺酰基]苯基]-2-甲基丙酰胺,XL-147; SAR245408) 目录号 : GC36917
A class I PI3K inhibitor
Cas No.:934526-89-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
XL147 is an inhibitor of class I PI3Ks (IC50s = 0.039, 0.036, 0.023, and 0.383 ?M for p110α, -δ, -γ, and -β, respectively).1 It is selective for class I PI3Ks over the class III PI3K vacuolar protein sorting 34 (Vps34; IC50 = 6.974 ?M), as well as DNA protein kinase (DNA-PK) and mammalian target of rapamycin (mTOR) (IC50s = 4.75 and >15 ?M, respectively). XL147 inhibits the proliferation of MCF-7 breast and PC3 prostate cancer cells (IC50s = 9.669 and 16.492 ?M, respectively). It reduces tumor growth in a BT474 breast cancer mouse xenograft model when administered alone or in combination with trastuzumab or lapatinib .2
1.Foster, P., Yamaguchi, K., Hsu, P.P., et al.The selective PI3K inhibitor XL147 (SAR245408) inhibits tumor growth and survival and potentiates the activity of chemotherapeutic agents in preclinical tumor modelsMol. Cancer Ther.14(4)931-940(2015) 2.Chakrabarty, A., Sánchez, V., Kuba, M.G., et al.Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitorsProc. Natl. Acad. Sci. USA109(8)2718-2723(2012)
| Cas No. | 934526-89-3 | SDF | |
| 别名 | 2-氨基-N-[3-[N-[3-[(2-氯-5-甲氧基苯基)氨基]喹喔啉-2-基]氨基磺酰基]苯基]-2-甲基丙酰胺,XL-147; SAR245408 | ||
| Canonical SMILES | CC(C)(N)C(NC1=CC=CC(S(=O)(NC2=NC3=CC=CC=C3N=C2NC4=CC(OC)=CC=C4Cl)=O)=C1)=O | ||
| 分子式 | C25H25ClN6O4S | 分子量 | 541.02 |
| 溶解度 | DMSO: ≥ 100 mg/mL (184.84 mM); Water: < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
| 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 | 1.8484 mL | 9.2418 mL | 18.4836 mL |
| 5 mM | 0.3697 mL | 1.8484 mL | 3.6967 mL |
| 10 mM | 0.1848 mL | 0.9242 mL | 1.8484 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 | ||||||||||
计算结果:
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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Phase I/II study of Pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer
Breast Cancer Res Treat 2015 Jan;149(1):151-61.PMID:25537644DOI:10.1007/s10549-014-3248-4.
This phase I/II dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and efficacy of the pan-class I phosphoinositide 3-kinase inhibitor Pilaralisib in combination with trastuzumab (Arm 1) or trastuzumab plus paclitaxel (Arm 2) in patients with HER2-positive metastatic breast cancer. Patients had progressed on prior trastuzumab (Arms 1 and 2) and received prior taxane (Arm 2). The MTD of Pilaralisib was determined using a 3 + 3 dose-escalation design (starting dose 200 mg once daily). Forty-two patients were enrolled (21 in each arm). Five patients had a dose-limiting toxicity (DLT; three in Arm 1 and two in Arm 2). Dose-limiting toxicities were rash (three patients) and neutropenia (two patients). The MTD of Pilaralisib was determined at 400 mg once daily in both arms. The most frequently reported treatment-related adverse events (AEs) were diarrhea (23.8 % in Arm 1 vs. 66.7 % in Arm 2), fatigue (14.3 vs. 42.9 %), and rash (33.3 vs. 38.1 %). The most frequently reported treatment-related grade ≥3 AEs were erythematous rash (9.5 %) in Arm 1 and diarrhea, peripheral neuropathy, and neutropenia (14.3 % each) in Arm 2. Steady-state Pilaralisib exposure was similar to previous studies with Pilaralisib monotherapy. No responses occurred in Arm 1; four of 20 evaluable patients (20 %) in Arm 2 had a partial response. Observed PIK3CA mutations in cell-free circulating DNA did not correlate with response. Pilaralisib in combination with trastuzumab with or without paclitaxel had an acceptable safety profile in metastatic HER2-positive breast cancer, with clinical activity in the paclitaxel arm.
Phase I Trial of a Tablet Formulation of Pilaralisib, a Pan-Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors
Oncologist 2018 Apr;23(4):401-e38.PMID:29593099DOI:10.1634/theoncologist.2017-0691.
Lessons learned: A phase I study of the pan-class I phosphoinositide 3-kinase inhibitor Pilaralisib (in capsule formulation) in advanced solid tumors established the maximum tolerated dose as 600 mg once daily.The current study investigated Pilaralisib in tablet formulation.Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity.Based on pharmacokinetic data, the recommended phase II dose of Pilaralisib tablets was established as 400 mg once daily. Background: A phase I trial of Pilaralisib, an oral pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, established the maximum tolerated dose (MTD) of the capsule formulation in patients with advanced solid tumors as 600 mg once daily. This phase I study investigated Pilaralisib in tablet formulation. Materials and methods: Patients with advanced solid tumors received Pilaralisib tablets (100-600 mg once daily). Primary endpoints were MTD and safety; secondary and exploratory endpoints included pharmacokinetics (PK), pharmacodynamics, and efficacy. Results: Twenty-two patients were enrolled. No dose-limiting toxicities (DLTs) were reported. The most common treatment-related adverse events were diarrhea (40.9%), fatigue (40.9%), decreased appetite (22.7%), and hyperglycemia (22.7%). Pilaralisib plasma exposure did not appear to increase dose-proportionally. Steady-state exposure was higher with Pilaralisib tablet formulation at 400 mg than with Pilaralisib capsule formulation at 400 or 600 mg (mean area under the curve [AUC0-24] 2,820,000 ng × h/mL vs. 2,653,000 and 1,930,000 ng × h/mL, respectively). Of 18 evaluable patients, 2 (11.1%) had a partial response (PR). Conclusion: Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity. MTD was not determined. The recommended phase II dose for Pilaralisib tablets, based on PK data, was 400 mg once daily.
Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147) in Combination with Paclitaxel and Carboplatin in Patients with Solid Tumors
Oncologist 2017 Apr;22(4):377-e37.PMID:28275119DOI:10.1634/theoncologist.2016-0257.
Lessons learned: Despite involvement of PI3K pathway activation in tumorigenesis of solid tumors, single-agent PI3K inhibitors have shown modest clinical activity.Preclinical evidence suggests that combining PI3K pathway inhibitors and chemotherapy can enhance antitumor effects.In patients with solid tumors, the PI3K inhibitor Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin.Further clinical evaluation is warranted to identify effective combination strategies with PI3K pathway inhibitors. Background: Pilaralisib (SAR245408) is an oral, pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I dose-escalation study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of Pilaralisib in capsule and tablet formulations, administered in combination with paclitaxel and carboplatin in patients with advanced solid tumors. Methods: A 3 + 3 design was used. Pilaralisib was administered once daily (QD); paclitaxel (up to 175 mg/m2) and carboplatin (up to area under the curve [AUC] of 6) were administered on day 1 of 21-day cycles. An MTD expansion cohort of patients with endometrial carcinoma was included. Results: Fifty-eight patients were enrolled. Six patients (10.3%) had dose-limiting toxicities, of which only rash (two patients, 3.4%) occurred in more than one patient. The MTD of Pilaralisib tablets in combination with paclitaxel and carboplatin was determined to be 200 mg QD. The most frequently reported adverse events (AEs) of any grade were neutropenia (67.2%) and thrombocytopenia (67.2%). PK data showed no interaction between Pilaralisib and paclitaxel/carboplatin. Tumor tissue showed moderate inhibition of PI3K and mitogen-activated protein kinase (MAPK) pathways. Seven of 52 evaluable patients had a partial response (PR; 13.5%). Conclusion: Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin in solid tumors. The Oncologist 2017;22:377-378.
Phase I dose-escalation study of Pilaralisib (SAR245408, XL147), a pan-class I PI3K inhibitor, in combination with erlotinib in patients with solid tumors
Oncologist 2015 Mar;20(3):245-6.PMID:25669662DOI:10.1634/theoncologist.2014-0449.
Background: This phase I study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of Pilaralisib (SAR245408), an oral pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, in combination with erlotinib, an epidermal growth factor receptor (EGFR) inhibitor. Methods: In a 3 + 3 dose-escalation study, patients with advanced solid tumors received Pilaralisib capsules once daily (21 days per 28-day cycle; 50-600 mg) plus erlotinib tablets once daily (28 days per 28-day cycle; 100 or 150 mg). An MTD expansion cohort of patients with non-small cell lung cancer who had previously received treatment with an EGFR inhibitor was included. Results: Thirty-five patients were enrolled. Only one patient had an EGFR activating mutation. One dose-limiting toxicity was reported (grade 4 drug reaction or rash with eosinophilia and systemic symptoms). MTD was Pilaralisib 400 mg plus erlotinib 150 mg. The most commonly reported treatment-related adverse events were rash (62.9%), diarrhea (42.9%), and fatigue (40.0%). Pilaralisib PK findings were consistent with previous studies, suggesting erlotinib had no effect on Pilaralisib pharmacokinetics. Pharmacodynamic analyses indicated moderate inhibition of PI3K, mitogen-activated protein kinase, and EGFR pathways. Of 27 evaluable patients, one had a partial response (3.7%) and 14 (51.9%) had stable disease. There was no association between molecular alterations of PI3K pathway components and clinical activity. Conclusion: Pilaralisib plus erlotinib had limited antitumor activity. Safety findings were similar to recent studies of single-agent Pilaralisib or other PI3K inhibitors.
Phase I safety and pharmacokinetic dose-escalation study of Pilaralisib polymorph E, a phosphoinositide 3-kinase inhibitor in tablet formulation, in patients with solid tumors or lymphoma
Cancer Chemother Pharmacol 2016 Jul;78(1):83-90.PMID:27169794DOI:10.1007/s00280-016-3056-0.
Purpose: Pilaralisib (SAR245408), a pan-class I PI3K inhibitor, has been investigated in Phase I/II trials in several solid tumors and lymphomas in capsule and tablet formulations of polymorph A (capsule-A and tablet-A). This Phase I study was conducted to determine the recommended Phase II dose (RP2D) of a more thermodynamically stable form of Pilaralisib (polymorph E), in tablet formulation (tablet-E), in patients with advanced solid tumors or relapsed/refractory lymphoma. Methods: A modified '3 + 3' dose-escalation design was employed. Patients received Pilaralisib once daily (QD; starting dose 400 mg) for two 28-day cycles. Primary endpoints were safety and pharmacokinetics (PK). Exploratory endpoints were pharmacodynamics and efficacy. Results: Eighteen patients were enrolled: Six patients received Pilaralisib 400 mg QD and 12 patients received Pilaralisib 600 mg QD. Two patients in the 600 mg QD cohort had dose-limiting toxicities (DLTs) (one patient with Grade 3 maculopapular rash and one patient with Grade 3 generalized rash and Grade 4 lipase increased). The most frequently occurring treatment-related, treatment-emergent adverse events were decreased appetite (22 %), dry skin (22 %), nausea (22 %) and vomiting (22 %). In PK analyses, individual exposures observed with 600 mg tablet-E were within the range of data at steady state from previous studies of 400 mg tablet-A and 600 mg capsule-A. Five patients (28 %) had stable disease as best response. Conclusions: With Pilaralisib tablet-E, the RP2D was 600 mg QD, drug exposure was similar to the 400 mg tablet-A and 600 mg capsule-A formulations, and safety was consistent with the known safety profile of Pilaralisib.