MRTX0902

MRTX0902 is an orally active and potent SOS1 inhibitor with an IC 50 of 46 nM (WO2021127429A1; Example 12-10) In Vitro MRTX0902 (compound 32) (1 μM; 0, 2, 4, 8, 15, and 30 minutes) shows a moderate Cl int value of 195 mL/min/kg in human liver microsome and a low lipophilicity with cLogP of 3.4. MRTX0902 displays high selectivity on SOS1 (K i =2 nM) over SOS2 and EGFR (both K i values >10,000 nM), MRTX0902 inhibits MKN1 cells with an IC 50 value of 29 nM. MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo MRTX0902 (compound 32) (25, 50 mg/kg; p.o.; twice daily; 25 d) shows anti-tumor effect in mouse model and results tumor regression . MRTX0902 (1-3 mg/kg for i.v. or 10-30 mg/kg for p.o.; single dose) exhibits good brain penetrance, low clearance, and high bioavailability . PK Parameters for MRTX0902 across Species Parameter Route Dose (mg/kg) Cl (mL/min/kg) V d,ss (L/kg) T 1/2 (iv) (h) F (%) Mouse IV/PO 3/30 4.4 0.28 1.3 69 Rat IV/PO 1/10 14.6 0.28 0.62 83 Dog IV/PO 2/10 7.6 0.48 0.86 38 MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Female CD-1 mice Dosage: 50 mg/kg Administration: Oral gavage; twice daily; 1 day Result: Resulted free drug exposure in the brain as well as the efflux ratio in the Caco-2 assay (ER = 1.5). Showed short half-life of the compound in mice (T 1/2 = 1.3 h). Animal Model: MIA PaCa-2 xenograft model in mouse Dosage: 25 mg/kg; 50 mg/kg Administration: Oral gavage; twice daily; 25 days Result: Reduced tumor growth by 41% and 53% at 25 mg/kg and 50 mg/kg administration. Form:Solid IC50& Target:KRAS-SOS1 46 nM (IC 50 )

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