MRTX9768 hydrochloride is a potent, selective, orally active, first-in-class PRMT5-MTA complex inhibitor^[1].

PRMT5•MTA^[1]

MRTX9768 inhibits SDMA and cell proliferation in HCT116 MTAP-del cells (SDMA IC₅₀ 3 nM; prolif. IC₅₀ 11 nM) with marked selectivity over HCT116 MTAP-WT cells (SDMA IC₅₀ 544 nM; prolif. IC₅₀ 861 nM)^[1].
MRTX9768 (0-250 nM) results in LU99 SDMA inhibition maintaining after 3-hr drug treatment followed by 4-day washout (exhibiting tight binding and prolonged PRMT5•MTA occupancy)^[3].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

In xenograft studies, oral administration of MRTX9768 demonstrates dose-dependent inhibition of SDMA in MTAP-del tumors, with less SDMA modulation observed in bone marrow^[1].
MRTX9768 selectively targets MTAP/CDKN2A-deleted tumors (such as glioblastoma)^[1][2].
MRTX9768 (PO dose 30 mg/kg in CD-1 mouse and beagle dog, 10 mg/kg in cynomolgus monkey) has a favorable ADME profile (>50% bioavailability in mice and dogs, moderate to high clearance, No changes in RBC parameters when administered well above efficacious concentrations (1000 mg/kg))^[3].
MRTX9768 (100 mg/kg, orally, BID, 6/21 days) results in SDMA inhibition maintaining 3 days after dosing is stopped^[3].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

460.89

C₂₄H₁₈ClFN₆O

Room temperature in continental US; may vary elsewhere.

-20°C, sealed storage, away from moisture and light

*In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture and light)

In Vitro: 

H₂O : 40 mg/mL (86.79 mM; Need ultrasonic)

DMSO : 19 mg/mL (41.22 mM; Need ultrasonic)

*

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, 6 months; -20°C, 1 month (sealed storage, away from moisture and light)。-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。

In Vivo:

请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液，再依次添加助溶剂：

——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用； 以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶

• 1.

  请依序添加每种溶剂： 10% DMSO    40% PEG300    5% Tween-80    45% saline

  Solubility: ≥ 4.5 mg/mL (9.76 mM); Clear solution

  此方案可获得 ≥ 4.5 mg/mL (9.76 mM，饱和度未知) 的澄清溶液。

  以 1 mL 工作液为例，取 100 μL 45.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。

  将 0.9 g 氯化钠，完全溶解于 100 mL ddH₂O 中，得到澄清透明的生理盐水溶液

• 2.

  请依序添加每种溶剂： 10% DMSO    90% (20% SBE-β-CD in saline)

  Solubility: ≥ 4.5 mg/mL (9.76 mM); Clear solution

  此方案可获得 ≥ 4.5 mg/mL (9.76 mM，饱和度未知) 的澄清溶液。

  以 1 mL 工作液为例，取 100 μL 45.0 mg/mL 的澄清 DMSO 储备液加到 900 μL 20% 的 SBE-β-CD 生理盐水水溶液中，混合均匀。

  将 2 g 磺丁基醚 β-环糊精加入 5 mL 生理盐水中，再用生理盐水定容至 10 mL，完全溶解，澄清透明
• 3.

  请依序添加每种溶剂： 10% DMSO    90% corn oil

  Solubility: ≥ 4.5 mg/mL (9.76 mM); Clear solution

  此方案可获得 ≥ 4.5 mg/mL (9.76 mM，饱和度未知) 的澄清溶液，此方案不适用于实验周期在半个月以上的实验。

  以 1 mL 工作液为例，取 100 μL 45.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。

• [1]. Christopher R. Smith, et al. Abstract LB003: Fragment based discovery of MRTX9768, a synthetic lethal-based inhibitor designed to bind the PRMT5-MTA complex and selectively target MTAP/CDKN2A-deleted tumors. AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA.

  [2]. Yingqing Chen, et al. Targeting protein arginine methyltransferase 5 in cancers: Roles, inhibitors and mechanisms. Biomed Pharmacother. 2021 Oct 4;144:112252.

  [3]. Matthew A. Marx, et al. Fragment-based discovery of MRTX9768, a synthetic lethal- based inhibitor designed to bind the PRMT5•MTA complex and selectively target MTAPDEL tumors. AACR ANNUAL MEETING 2021:APRIL 10-15, 2021 AND MAY 17-21, 2021.