sar405838 and Neoplasms

In tumor cells, p53 is always inactivated due to the mutation or deletion of TP53 gene or inhibited by the overexpressed MDM2. Small-molecule induced restoring of p53 function by blocking MDM2-p53 protein-protein interactions has been highly pursued as an attractive therapeutic strategy for cancer therapy. To date, a large number of small-molecule inhibitors have been identified based on the compact and well-defined MDM2-p53 interactions, of which SAR405838, MK-8242, DS-3032b, NVP-CGM097, RG7112, HDM201, RG7388, ALRN-6924 and AMG 232 are undergoing clinical assessment at different phases for cancer therapy. This review is focused on the discovery and development of piperidinone-based MDM2-p53 inhibitors for cancer therapy, including the identification of hit compounds, hit-to-lead optimizations, binding models of ligands in the active site of MDM2, metabolic studies, and preclinical data of advanced piperidinone-based MDM2-p53 inhibitors. Additionally, acquired resistance of MDM2 inhibitors and potential toxicity toward normal tissues are briefly discussed.

Topics: Dose-Response Relationship, Drug; Humans; Ligands; Molecular Structure; Neoplasms; Piperidones; Protein Binding; Proto-Oncogene Proteins c-mdm2; Structure-Activity Relationship; Tumor Suppressor Protein p53

MDM2 is a primary cellular inhibitor of p53. It inhibits p53 function by multiple mechanisms, each of which, however, is mediated by their direct interaction. It has been proposed that small-molecule inhibitors designed to block the MDM2-p53 interaction may be effective in the treatment of human cancer retaining wild-type p53 by reactivating the p53 tumor suppressor function. Through nearly two decades of intense efforts, a number of structurally distinct, highly potent, nonpeptide, small-molecule inhibitors of the MDM2-p53 interaction (MDM2 inhibitors) have been successfully designed and developed, and at least seven such compounds have now been advanced into human clinical trials as new anticancer drugs. This review offers a perspective on the design and development of MDM2 small-molecule inhibitors and discusses early clinical data for some of the MDM2 small-molecule inhibitors and future challenges for the successful clinical development of MDM2 inhibitors for cancer treatment.

Topics: Animals; Antineoplastic Agents; Humans; Imidazolines; Indoles; Neoplasms; Protein Binding; Proto-Oncogene Proteins c-mdm2; Spiro Compounds; Tumor Suppressor Protein p53

Design of small-molecule inhibitors (MDM2 inhibitors) to block the MDM2-p53 protein-protein interaction has been pursued as a new cancer therapeutic strategy. In recent years, potent, selective, and efficacious MDM2 inhibitors have been successfully obtained and seven such compounds have been advanced into early phase clinical trials for the treatment of human cancers. Here, we review the design, synthesis, properties, preclinical, and clinical studies of these clinical-stage MDM2 inhibitors.

Topics: Animals; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Models, Molecular; Molecular Structure; Neoplasms; Protein Binding; Proto-Oncogene Proteins c-mdm2; Small Molecule Libraries; Structure-Activity Relationship; Tumor Suppressor Protein p53

This phase I, open-label, dose-escalation study evaluated the safety, pharmacokinetics and pharmacodynamics of combination therapy with the HDM2 inhibitor SAR405838 and the MEK1/2 inhibitor pimasertib administered orally once daily (QD) or twice daily (BID) in locally advanced or metastatic solid tumours (NCT01985191).. Patients with locally advanced or metastatic solid tumours with documented wild-type TP53 and RAS or RAF mutations were enroled. A 3 + 3 dose-escalation design was employed. The primary objective was to assess maximum tolerated dose (MTD).. Twenty-six patients were treated with SAR405838 200 or 300 mg QD plus pimasertib 60 mg QD or 45 mg BID. The MTD was SAR405838 200 mg QD plus pimasertib 45 mg BID. The most common dose-limiting toxicity was thrombocytopenia. The most frequently occurring treatment-related adverse events were diarrhoea (81%), increased blood creatine phosphokinase (77%), nausea (62%) and vomiting (62%). No significant drug-drug interactions were observed. The biomarkers MIC-1 and pERK were, respectively, upregulated and downregulated in response to study treatment. In 24 efficacy-evaluable patients, one patient (4%) had a partial response and 63% had stable disease.. The safety profile of SAR405838 and pimasertib combined was consistent with the safety profiles of both drugs. Preliminary antitumour activity was observed.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Female; Gene Expression Regulation, Neoplastic; Humans; Indoles; Male; MAP Kinase Kinase Kinases; Maximum Tolerated Dose; Middle Aged; Neoplasms; Niacinamide; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-mdm2; Proto-Oncogene Proteins p21(ras); Spiro Compounds; Thrombocytopenia; Tumor Suppressor Protein p53

In tumours with wild-type TP53, the tumour-suppressive function of p53 is frequently inhibited by HDM2. This phase I, dose-escalating study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and pharmacodynamics of SAR405838, an HDM2 inhibitor, in patients with advanced solid tumours (NCT01636479).. In dose escalation, patients with any locally advanced/metastatic solid tumour with TP53 mutation prevalence below 40%, or documented as TP53 wild-type, were eligible. In the MTD expansion cohort, only patients with de-differentiated liposarcoma were included. Primary end-points were MTD and efficacy in the MTD expansion cohort. Secondary end-points included safety, pharmacokinetics and pharmacodynamics biomarkers.. Seventy-four patients were treated with SAR405838 (50-800 mg once daily [QD], 800-1800 mg weekly and 1800 mg twice weekly). Two patients treated with SAR405838 400 mg QD had thrombocytopaenia as a dose-limiting toxicity (DLT). The MTD for the QD schedule of SAR405838 was 300 mg QD. No DLTs were observed with the weekly schedule; one patient had a DLT of nausea with the 1800 mg twice-weekly dose. Treatment with SAR405838 was associated with increased plasma MIC-1, reflecting p53 pathway activation. In the de-differentiated liposarcoma MTD cohort, 89% of the patients had HDM2 amplification at baseline and no TP53 mutations were observed; best response was stable disease in 56% and progression-free rate at 3 months was 32%.. SAR405838 had an acceptable safety profile with limited activity in patients with advanced solid tumours. The MTD of SAR405838 was 300 mg QD; MTD was not reached with the weekly schedule.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Fatigue; Female; Gastrointestinal Neoplasms; Humans; Indoles; Liposarcoma; Lung Neoplasms; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Nausea; Neoplasms; Proto-Oncogene Proteins c-mdm2; Skin Neoplasms; Spiro Compounds; Thrombocytopenia; Vomiting; Young Adult

We previously reported the design of spirooxindoles with two identical substituents at the carbon-2 of the pyrrolidine core as potent MDM2 inhibitors. In this paper we describe an extensive structure-activity relationship study of this class of MDM2 inhibitors, which led to the discovery of 60 (AA-115/APG-115). Compound 60 has a very high affinity to MDM2 (K

Topics: Animals; Antineoplastic Agents; Bone and Bones; Bone Neoplasms; Bridged Bicyclo Compounds; Cell Line, Tumor; Drug Discovery; Halogenation; Humans; Indoles; Leukemia; Mice; Molecular Docking Simulation; Neoplasms; Osteosarcoma; Proto-Oncogene Proteins c-mdm2; Pyrrolidines; Rats; Structure-Activity Relationship