Abstract 4638: NVP-CGM097: a novel p53-Mdm2 inhibitor exhibiting potent antitumor activity in mouse models of human cancer

Abstract

Although functional inactivation of the tumor suppressor p53 is a frequent genetic event, half of all human tumors express wild-type p53. Stabilization of p53 by antagonizing its negative regulator mouse double minute 2 (Mdm2) leads to selective induction of the p53 pathway, thus offering a promising therapeutic opportunity. NVP-CGM097 binds in the p53 pocket on the surface of Mdm2 and effectively disrupts the interaction between p53 and Mdm2. The aim of this study was to determine the pharmacokinetic (PK), pharmacodynamic (PD) and efficacy profile of this novel p53-Mdm2 inhibitor in mouse models of human cancer. During the medicinal chemistry discovery efforts, the compound series was optimized for oral administration. The selected compound, NVP-CGM097, was well absorbed in mice where the maximum plasma concentration (Tmax) was observed about 3 hours post dose followed by a prolonged absorption phase. PD effects were determined by measuring the expression levels of p53 target genes including p21, PUMA and Mdm2 in tumors. The expression levels of p53 target genes correlated with the concentrations of NVP-CGM097 demonstrating a good PK/PD relationship. Optimal treatment schedules were investigated in the Mdm2-amplified, p53 wild-type osteosarcoma xenograft model SJSA-1. Interestingly, various schedules were highly efficacious at well-tolerated dose levels. Tumor regression was observed when NVP-CGM097 was administered in schedules ranging from daily to twice per week with no adverse effects. Following dose optimization studies, potent anti-tumor efficacy was observed in a range of p53 wild-type expressing xenograft models including Mdm2 non-amplified orthotopic AML as well as well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcomas. Overall, we demonstrate that the novel p53-Mdm2 inhibitor NVP-CGM097 has a good PK profile and affects PD markers in human tumors leading to tumor regression at well-tolerated dose levels. These data strongly support clinical development of NVP-CGM097. Citation Format: Stéphane Ferretti, Marjorie Berger, Ramona Rebmann, Francesca Santacroce, Dario Sterker, Michael Jensen, Keiichi Masuya, Sébastien Jeay. NVP-CGM097: a novel p53-Mdm2 inhibitor exhibiting potent antitumor activity in mouse models of human cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4638. doi:10.1158/1538-7445.AM2014-4638

A distinct p53 target gene set predicts for response to the selective p53–HDM2 inhibitor NVP-CGM097

“…As to compare with Nutlin 3a, NVP-CGM097 and NVP-CFC218 show differences in binding mode within the p53 binding site of HDM2 (Jeay et al, 2014; Valat et al, 2014, manuscript in preparation), which allows better in vitro and in vivo on-target potency, more favorable drug-like properties, and improved in vivo behavior of this compound family (Ferretti et al, 2014; Jeay et al, 2014). NVP-CGM097 and NVP-CFC218 were first tested in cell-free assays, where both were shown to selectively inhibit p53–HDM2 binding.…”

“…The newly discovered close analogs, NVP-CGM097 and NVP-CFC218 ( Figure 1A ), are both members of a novel chemical class (dihydroisoquinolinones) which differs from Nutlin analogs (e.g., Nutlin 3a and RO5045337/RG7112) or other p53–HDM2 inhibitors currently being tested in the clinic (e.g., RO5503781/RG7388, SAR405838/MI-773, AMG 232, DS3032b) ( Masuya et al, 2014 , manuscript in preparation). As to compare with Nutlin 3a, NVP-CGM097 and NVP-CFC218 show differences in binding mode within the p53 binding site of HDM2 ( Jeay et al, 2014 ; Valat et al, 2014 , manuscript in preparation), which allows better in vitro and in vivo on-target potency, more favorable drug-like properties, and improved in vivo behavior of this compound family ( Ferretti et al, 2014 ; Jeay et al, 2014 ). NVP-CGM097 and NVP-CFC218 were first tested in cell-free assays, where both were shown to selectively inhibit p53–HDM2 binding.…”

Inhibition of Wild-Type p53-Expressing AML by the Novel Small Molecule HDM2 Inhibitor CGM097

“…In a cell proliferation assay, CGM097 inhibited the growth of HCT-116 p53 WT cells with a GI 50 of 454 nM and of HCT-116 p53-null cells with a GI 50 of 15,983 nM (38, 40). In contrast to HDM2 inhibitors, such as nutlin-3, which have been shown to display limited bioavailability in oral formulations in preclinical models (41), CGM097 is well-absorbed with a moderate to high oral bioavailability ranging from 57 to 81% across multiple animal species tested (mouse, rat, dog and monkey) (38, 42). In addition, CGM097 displays an excellent PK profile, low human intrinsic clearance, and exceptional ability to selectively inhibit p53/Mdm2 over p53/Mdm4 with negligible activity against p53 null cells 38,40,42 .…”

“…In contrast to HDM2 inhibitors, such as nutlin-3, which have been shown to display limited bioavailability in oral formulations in preclinical models (41), CGM097 is well-absorbed with a moderate to high oral bioavailability ranging from 57 to 81% across multiple animal species tested (mouse, rat, dog and monkey) (38, 42). In addition, CGM097 displays an excellent PK profile, low human intrinsic clearance, and exceptional ability to selectively inhibit p53/Mdm2 over p53/Mdm4 with negligible activity against p53 null cells 38,40,42 . Lastly, CGM097 demonstrates dose-dependent anti-tumor activity in human primary tumor xenografts in a p53 dependent manner (38, 40, 42).…”

“…In addition, CGM097 displays an excellent PK profile, low human intrinsic clearance, and exceptional ability to selectively inhibit p53/Mdm2 over p53/Mdm4 with negligible activity against p53 null cells 38,40,42 . Lastly, CGM097 demonstrates dose-dependent anti-tumor activity in human primary tumor xenografts in a p53 dependent manner (38, 40, 42). …”