RMC-5552

RMC-5552 is a potent and selective mTORC1 inhibitor. RMC-5552 inhibits phosphorylation of mTORC1 pS6K and p4EBP1 with IC 50 s of 0.14 nM and 0.48 nM, respectively. RMC-5552 shows much lower pAKT inhibition (IC 50 of 19 nM), resulting in mTORC1/mTORC2 selectivity approaching 40-fold. RMC-5552 has anti-cancer activity In Vitro The presence of FKBP12, whose recruitment would only be observed in the presence of the FKBP12-FRB allosteric modality of RMC-5552. Density for RMC-5552 is evident at the interface between FKBP12 and the FRB domain of mTOR. RMC-5552 makes hydrogen bonds to the backbone of G2238 and V2240, the “hinge” of mTOR, via the 4-aminopyrazolo[3,4-d]pyrimidine core, and the 2-aminobenzoxazole makes hydrogen-bonding interactions to E2190 and K2187. MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo RMC-5552 (1-10 mg/kg; i.p.; once weekly; for 28 days) exhibits antitumor activity in a human xenograft model of MCF-7 breast cancer in mice in vivo . PK Parameters of RMC-5552 38 in Mice at 1 mg/kg via IP Administration compounds T max (h) C max (ng/mL) C max (μM) AUC last (μg/mL × h) AUC last (μM × h) t 1/2 (h) 38 RMC-5552 2.0 ± 0.0 5667 ± 1106 3.19 ± 0.62 46 089 ± 5320 25.9 ± 3.0 4.8 ± 0.4 MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Female Balb/c nude mice (6-8 weeks of age) injected with MCF-7 cells Dosage: 1 mg/kg, 3 mg/kg, 10 mg/kg Administration: i.p.; once weekly; for 28 days Result: Resulted in a reduction in tumor volume. Form:Solid IC50& Target:mTORC1

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