LY3023414
(Synonyms: LY3023414) 目录号 : GC14371
LY3023414 (LY3023414) potently and selectively inhibits class I PI3K isoforms, DNA-PK, and mTORC1/2 with IC50s of 6.07 nM, 77.6 nM, 38 nM, 23.8 nM, 4.24 nM and 165 nM for PI3Kα, PI3Kβ, PI3Kδ , PI3Kγ, DNA-PK 和 mTOR, 分别。 LY3023414 在低纳摩尔浓度下有效抑制 mTORC1/2。
Cas No.:1386874-06-1
Sample solution is provided at 25 µL, 10mM.
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IC50: 64.9, 42.1, 10.6, and 19.1 nM for Akt1(pT308), Akt1 (pS473), P70S6(pT389), and S6RP(pS240/242), respectively.
LY3023414 is an ATP competitive inhibitor of the class I PI3K isoforms, mTOR and DNA-PK.
The phosphoinositide-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is one of the most frequently altered pathways in cancer cell growth and survival.
In vitro: In biochemical testing against approximately 266 kinases, LY3023414 was found to potently and selectively inhibit class I PI3K isoforms, mTORC1/2, as well as DNA-PK at low concentrations. In addition, inhibition of PI3K/AKT/mTOR signaling by LY3023414 led to G1 cell-cycle arrest and resulted in broad antiproliferative activity in cancer cell panel [1].
In vivo: LY3023414 showed high bioavailability and dose-dependent dephosphorylation of PI3K/AKT/mTOR pathway downstream substrates for 4 to 6 hours, indicating LY3023414's half-life of 2 hours. Moreover, equivalent total daily doses of LY3023414 given either once or twice daily could inhibit tumor growth to the similar extents in multiple xenograft models, demonstrating intermittent target inhibition was sufficient for antitumor activity [1].
Clinical trial: LY3023414 appears to be safe when administered as single agent up to 325 mg QD or 200 mg BID. Currently, LY3023414 is investigated in tumor-specific expansion cohorts for breast cancer, mesothelioma, Non-Hodgkin Lymphoma as well as NSCLC (Clinical trial information: NCT01655225).
Reference:
[1] Smith MC,Mader MM,Cook JA,et al. Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth. Mol Cancer Ther.2016 Oct;15(10):2344-2356.
Kinase experiment: | The selectivity and inhibitory potential of LY3023414 are assessed against a panel of 192 kinases in PC-3 cell lysates using the KiNativ platform and a panel of 102 kinases as purified enzymes from Cerep. Together, the 2 kinase panels covered approximately 266 unique kinases. These kinases are tested with three concentrations of LY3023414 to measure inhibition and calculate approximate IC50 values. The IC50 of LY3023414 for PI3Kα is measured using 5 nM recombinant human PI3Kα, 0.01 mM ATP with a 1.76 mM Triton X 100/0.04 mM PIP2/0.2 mM PS mixed micelle as the lipid substrate in a scintillation proximity assay (SPA) with neomycin-linked beads. The IC50 of LY3023414 for PI3Kβ is measured using a mixed micelle SPA format with 0.04 mM ATP with a 0.27 mM Triton X 100/0.05 mM PIP2/0.04 mM PA mixed micelle as the lipid substrate. The IC50s of PI3Kδ and PI3Kγand of DNA-PK are measured. The IC50 for mTOR is measured[1]. |
Cell experiment: | The CellTiter-Glo luminescent cell viability assay system is used to measure the antiproliferative effects of LY3023414 after 2 cell doublings on cells plated on plastic or incubated for 2 weeks in soft agar with a collection of standard cell lines and human patient–derived tumor xenografts passaged in nude mice. For the soft-agar assay, RKO and SK-OV-3 cells; MOLT-4 and L-363 cells; DLD-1, HCT-116, HCT-15, and NCI-H460 cells are used. These standard cell lines are genotyped by STR and matched to existing STR reference genotypes. Oncotest PDX models (including model MX1 originally derived at NCI) are characterized using the Affymetrix genome-wide human SNP Array 6.0 as well as whole-exome sequencing. Genetic identity analysis confirm that all PDX models are derived from independent patient samples. Combination studies are conducted in which LY3023414 is mixed with other therapeutic agents in fixed ratios of concentrations corresponding to the IC50 equivalents of each single agent. The combination index at 50% inhibition (CI50) is calculated[1]. |
Animal experiment: | Mice[1] Xenograft tumors are implanted subcutaneously in athymic nude, CD-1 nude mice, and NMRI athymic nude mice. B6.Cg-Tg(IghMyc)22Bri/J mice and C57BL/6NTac mice are used in the Eμ-myc transgenic orthotopic mutant PI3Kα E545K-driven leukemia model similar to the Akt1 E17K cancer model. LY3023414 is formulated in 1% HEC in distilled water containing 0.25% polysorbate 80 and 0.05% Dow-Corning Antifoam 1510-US and administered by oral gavage (final volume 0.2 mL) at the indicated doses and schedules. Efficacy and in vivo target inhibition studies are carried out after tumor volumes reach 150 to 200 mm3. Target inhibition studies are conducted at various time points after administration of a single dose of LY3023414 to mice harboring tumors. Tumors are harvested, flash frozen, lysed in MSD buffer, and then analyzed using the MSD-ELISA multiplex method. |
References: [1]. Wei L, et al. Genomic profiling is predictive of response to CDDP treatment but not to PI3K inhibition in bladder cancer patient-derived xenografts. Oncotarget. 2016 Nov 22;7(47):76374-76389. | |
| Cas No. | 1386874-06-1 | SDF | |
| 别名 | LY3023414 | ||
| 化学名 | (S)-8-(5-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-methoxypropyl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-one | ||
| Canonical SMILES | O=C(N(C1=C2C3=CC(C4=CC(C(O)(C)C)=CN=C4)=CC=C3N=C1)C)N2C[C@H](C)OC | ||
| 分子式 | C23H26N4O3 | 分子量 | 406.48 |
| 溶解度 | ≥ 40.6mg/mL in DMSO | 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 | 2.4601 mL | 12.3007 mL | 24.6015 mL |
| 5 mM | 0.492 mL | 2.4601 mL | 4.9203 mL |
| 10 mM | 0.246 mL | 1.2301 mL | 2.4601 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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。
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet