RMC-5552 (C09-1167-318)

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 activityIn VitroThe 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 VivoRMC-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:SolidIC50& Target:mTORC1. Specification: 0.95 Molecular Formula: C93H136N10O24 Molecular Weight: 1778.13 PubChem CID: 162640850 Isomeric SMILES: C[C@@H]1CC[C@H]2C[C@@H](/C(=C/C=C/C=C/[C@H](C[C@H](C(=O)[C@@H]([C@@H](/C(=C/[C@H]([C@@H](C[C@H](OC(=O)[C@@H]3CCCCN3C(=O)C(=O)[C@@]1(O2)O)[C@H](C)C[C@@H]4CC[C@H]([C@@H](C4)OC)OC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)N5CCC6=C(C5)C=CC(=C6)CN7C8=NC=NC(=C8C(=N7)C9=CC1=C(C=C9)OC(=N1)N)N)O)C)/C)O)OC)C)C)/C)OC