p53-MDM2 (IC50 = 6 nM)

In cancer cells expressing wild-type p53, isasanutlin inhibits cell proliferation with an IC50 of 30 nM and induces dose-dependent p53 stabilization, cell cycle arrest, as well as cell apoptosis.[1]
RG7388 displayed improved in vitro binding as well as cellular potency/selectivity. Thus, compound 12 was chosen for further studies. In cell-based mechanistic studies), RG7388 induced dose-dependent p53 stabilization, cell cycle arrest, and apoptosis in cancer cells expressing wild-type p53, consistent with a nongenotoxic p53 activation mechanism.[1]

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RG7388-induced apoptosis in SJSA osteosarcoma cells is delayed relative to drug exposure but does not require continuous treatment[2].

In initial efficacy testing, daily dosing at 30 mg/kg and twice a week dosing at 50 mg/kg of RG7388 were statistically equivalent in our tumor model. In addition, weekly dosing of 50 mg/kg was equivalent to 10 mg/kg given daily. The implementation of modeling and simulation on these data suggested several possible intermittent clinical dosing schedules. Further preclinical analyses confirmed these schedules as viable options.[2]

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RG7388 also achieved impressive in vivo efficacy against established human SJSA1 osterosarcoma xenografts in nude mice at significantly lower doses and exposures compared to RG7112[1].

The 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 1 mM DTT, and 0.02 or 0.2 mg/ml BSA buffer is used for the p53-MDM2 HTRF assay. Aliquots of small-molecule inhibitors are kept at 4°C in 96-deep-well plates as stock solutions of 10 mM DMSO. Just before testing, it is thawed and blended. A biotinylated p53 peptide and GST-MDM2 are incubated with the substance for an hour at 37°C. Following the addition of Eu-8044-streptavidin and Phycolink goat anti-GST (Type 1) allophycocyanin, an hour-long incubation at room temperature is required. Using the Envision fluorescence reader, plates are read. Data sets in duplicate or triplicate between plates are used to calculate IC50 values. Data is analyzed by XLfit4 (Microsoft) using a Sigmoidal Dose-Response Model with 4 Parameter Logistic Model and the equation Y= (A+ ((B-A)/ (1+ ((C/x)^D)))), where A and B are enzyme activity in the absence or presence of infinite inhibitor compound, respectively, C is the IC50, and D is the Hill coefficient.[1]

Tetrazolium dye assay is used to assess cell proliferation. The linear regression of a plot of the concentration versus percent inhibition's logarithm yields the concentration at which cell proliferation is 50% (IC50) or 90% (IC90) inhibited.[1]

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In vitro testing in cancer cell lines[2]
RG7388 was prepared at concentrations of 1 and 10 mmol/L in DMSO and stored in aliquots at −20°C. SJSA, RKO, HCT116, H460, A375, SK-MEL-5, SW480, MDA435, and HeLa cells were obtained from the ATCC. Cell lines were authenticated by short tandem repeat analysis through Promega authentication services. For in vitro studies, cells were cultured in their ATCC-designated media. Medium was supplemented with 10% FBS and 1% 200 nmol/L l-glutamine. To assess cell viability, cells were seeded at densities identified for best growth for a 5-day assay in 96-well plates in normal growth media. Serial dilutions of RG7388 (1–3 in fresh media) starting at 300 μmol/L were applied to wells (1–10) in triplicate for a final concentration range of 0.01 to 30 μmol/L and control wells were treated with 0.3% DMSO equivalent to DMSO at the highest RG7388 concentration. Cell respiration, as an indicator of cell viability, was measured by the reduction of MTT to formazan as previously described.
Percent apoptosis was determined as described in Tovar and colleagues. For Western blot analysis, cells were cultured in T-75 flasks (4 mL total volume at 5 × 105 cells/well) and incubated overnight at 37°C, 5% CO2. Cells were treated with 0.3 or 1.8 μmol/L of RG7388 or 0.1% DMSO as control. Treatment duration was 16 hours, and lysates were prepared before washout and at 4, 8, 24, and 48 hours after RG7388 washout.

Efficacy of Oral MDM2 Inhibitor RG7388 in the SJSA Human Osteosarcoma Xenograft Model [1]
Female SJSA tumor-bearing nude mice were orally administered daily doses of RG7388 and blood samples were collected in EDTA tubes from 2 animals/group/time point (1, 2, 4, 8 and 24 hours) after the first (acute PK) or last (chronic PK) dose. Plasma and tumor samples were prepared and analyzed for RG7388 by LC/MS/MS. Mean plasma concentrations were calculated from 2 animals/group/time point. S-9 Efficacy of Oral MDM2 Inhibitor RG7388 in the SJSA Human Osteosarcoma Xenograft Model The anti-tumor efficacy of RG7388 in the SJSA1 model was determined in female nude mice as reported in Tovar et al.1 In the current study, mice were randomized into treatment groups of 10 mice with similar mean tumor volumes of 190-230 mm3 . RG7388 was administered by gavage at doses from 12.5-50 mg/kg daily for two weeks.

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Efficacy of Oral MDM2 Inhibitor RG7388 in the SJSA Human Osteosarcoma Xenograft Model [1]
The anti-tumor efficacy of RG7388 in the SJSA1 model was determined in female nude mice as reported in Tovar et al.1 In the current study, mice were randomized into treatment groups of 10 mice with similar mean tumor volumes of 190-230 mm3 . RG7388 was administered by gavage at doses from 12.5-50 mg/kg daily for two weeks.

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Pharmacokinetic analysis[2]
To determine RG7388 plasma concentrations, blood samples were collected from female mice during in vivo antitumor studies. In each treatment group, on the first and/or last dosing day, blood samples (generally n = 2/time point) were collected at various predetermined time points ranging from 0.5 to 24 hours after the last dose. Pharmacokinetic assessment was performed via noncompartmental analysis using Watson v7.4, where parameters were calculated on the basis of the composite concentration–time data from each treatment group and sampling day. Sampling times were reported as nominal time, with concentrations below the limit of quantitation excluded. Parameters reported include plasma half-life (t1/2), Cmax, Tmax, and area under the plasma concentration–time curve from end of dosing to the last bleeding time point (AUC0–24 hours). The AUCs were calculated using the linear trapezoidal rule. The Cmax and Tmax values were taken directly from the plasma concentration–time profiles without extrapolations.

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In vivo activity studies in xenograft tumor models[2]
Athymic female nude mice (Crl:NU-Foxn1nu) were obtained from Charles River Laboratories. The health of all animals was monitored daily by gross observation and analyses of blood samples of sentinel animals. All animal experiments were performed in accordance with protocols approved by the Institutional Animal Care and Use Committee in our Association for Assessment and Accreditation of Laboratory Animal Care-accredited facility.
At 10 to 12 weeks of age, mice were implanted with a 1:1 mixture of human SJSA osteosarcoma cells (ATCC) suspended in phenol-free Matrigel and PBS. Mice were implanted in the right flank at a concentration of 5 × 106 cells in 0.2 mL total volume. At approximately day 10, animals were randomized according to tumor volume, so that all groups of 10 randomized mice had similar starting mean tumor volumes of 100 to 250 mm3.
Tumor measurements and weights were taken two to three times per week. TGI was calculated from percent change in mean tumor volume compared with the control group. Average percent weight change was used as a surrogate endpoint for tolerability in the experiment. Animals in each group were continuously followed beyond the last day of treatment to see whether tumor regrowth would occur. In this second phase of analysis, survival was calculated using a cutoff individual tumor volume of 1,500 mm3 as a surrogate for mortality. The increase in lifespan (ILS) was calculated as a percentage using the formula: [(median day of death in treated tumor-bearing mice) − (median day of death in control tumor-bearing mice)]/median day of death in control tumor-bearing mice × 100. Statistical analysis was performed as previously described.
RG7388 was administered as an amorphous solid dispersion microbulk precipitate powder containing 30% drug substance and 70% hydroxypropyl methylcellulose acetate succinate polymer that was reconstituted immediately before administration as a suspension in Klucel/Tween, and remaining suspension was discarded after dosing.

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Formulated in 30% drug substance and 70% hydroxypropyl methylcellulose acetate succinate polymer; 25 mg/kg; p.o.

Athymic female nude mice (Crl:NU-Foxn1nu) bearing SJSA human osteosarcoma xenograft model

Pharmacokinetics [3]
Idasanutlin peak concentrations typically occurred 6 to 8 h after oral administration without food, and declined thereafter, with terminal half-life of ≈30 h (Fig. 2A). Exposure was approximately dose proportional after the first dose (i.e., day 1) and following repeat dosing (i.e., day 3 for QD × 3 regimens, day 5 for QD × 5 regimens), although increases appeared to be less than dose proportional at doses above 600 mg, suggesting a saturation in intestinal absorption at this dose level (Fig. 2B). However, inter-patient variability in exposure was high with all dosing regimens (Fig. 2B). Exposure was approximately twofold higher on the final day of QD × 3 and QD × 5 dosing compared with the first dose (Fig. 2B), but there was no accumulation with QW × 3 dosing (data not shown). For a specified daily dose, cumulative idasanutlin exposure over the whole 28-day dosing cycle was greatest with a QD × 5 regimen, reflecting the higher total dose administered (i.e., 5 days of dosing vs. 3 days of dosing or 3 single doses).

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Food effects on idasanutlin pharmacokinetics [3]
Ten patients received 800-mg doses of idasanutlin, either with a high-fat/high-calorie meal or while fasted. Dosing employed a half-replicate, crossover design, which resulted in 15 pairs of fed versus fasted data from the 10 patients. On average, idasanutlin exposure was higher when taken with food (mean maximum plasma concentration was 14% higher and area under the curve extrapolated to infinity was 43% higher), but variability was high and as the 90% confidence intervals encompassed unity, it was concluded that food had no clinically meaningful effect on idasanutlin exposure (Online Resource Table S7; Fig. 2C).

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Pharmacodynamic analysis [3]
After idasanutlin dosing, circulating macrophage inhibitory cytokine 1 (MIC-1) levels increased generally in a dose-exposure–dependent manner (Fig. 2D). Consequently, trends in MIC-1 responses to treatment mirrored trends in idasanutlin exposure, as described in Population PK/PD Analysis section.
Sixteen of the 31 patients (51.6%) evaluated by positron emission tomography analysis for changes in tumor proliferation rates with idasanutlin treatment achieved a partial proliferative response as their best percentage maximum standardized uptake value change from baseline during cycle 1, indicating a decrease of ≥ 25% (Online Resource Fig. S2).

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Population PK/PD analysis [3]
Simulations with the indirect PK/MIC-1 model (Online Resource Supplementary Methods) indicated that despite some high variability, the release of MIC-1 following idasanutlin treatment is concentration dependent; the higher the idasanutlin concentrations, the higher the release of MIC-1. Weekly dosing with idasanutlin resulted in lower maximum release but a more sustainable effect on MIC-1 over the 28-day treatment cycle compared with a daily regimen (for the same level of dose) (Fig. 3).

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Idasanutlin (RG7388) is a MDM2 (murine double minute 2) inhibitor that is being investigated for its anticancer effects, particularly in tumors with wild-type TP53 (e.g., acute myeloid leukemia, solid tumors). Here’s an overview of its pharmacokinetics (PK) based on available preclinical and clinical data:
1. Absorption
Route of Administration: Oral (tablet formulation).
Bioavailability: Limited data, but oral absorption is moderate (~30-50% in preclinical models).
Food Effect: High-fat meals may significantly increase absorption (observed in clinical trials). Thus, it is often administered with food to enhance bioavailability.

2. Distribution
Protein Binding: Highly protein-bound (>99%, primarily to albumin).
Volume of Distribution (Vd): Not well characterized, but likely moderate due to high protein binding.
Tissue Penetration: Preclinical data suggest distribution into tumor tissues, but CNS penetration is likely limited.

3. Metabolism
Primary Pathway: Hepatic metabolism, primarily via CYP3A4 (major) and UGT1A1/UGT1A3 (glucuronidation).
Metabolites: Several oxidative and conjugated metabolites (mostly inactive or weakly active).
Drug-Drug Interactions (DDIs):
CYP3A4 inducers (e.g., rifampin) → May decrease idasanutlin exposure.
CYP3A4 inhibitors (e.g., ketoconazole) → May increase idasanutlin exposure.
UGT inhibitors (e.g., atazanavir) → Potential increase in exposure.

4. Elimination
Half-life (t½): ~4–8 hours (variable between patients).
Clearance: Primarily hepatic with biliary excretion.
Excretion: Mostly fecal (~70-80%), with minimal renal excretion (<5%).

5. Pharmacokinetic Variability
Interpatient Variability: High, possibly due to differences in CYP3A4/UGT activity, food effects, and protein binding.
Dose Proportionality: Nonlinear PK at higher doses (saturation of absorption or metabolism).
6. Special Populations
Hepatic Impairment: Expected to significantly increase exposure (not well studied).
Renal Impairment: Unlikely to have a major effect (minimal renal excretion).
Pediatric/Elderly: Limited data; studies are ongoing.
7. Clinical Implications
Optimal Dosing: Typically given once daily or intermittently (e.g., 5 days on/2 days off) to manage toxicity (e.g., gastrointestinal effects, thrombocytopenia).
Therapeutic Drug Monitoring (TDM): May be useful due to high PK variability.

Summary Table of Idasanutlin PK
Parameter Characteristics
Route Oral (with food)
Bioavailability Moderate (~30-50%)
Protein Binding >99% (albumin)
Metabolism CYP3A4, UGT1A1/1A3
Half-life ~4–8 hours
Excretion Feces (~70-80%), urine (<5%)
Key DDIs CYP3A4 inducers/inhibitors

Ongoing Research
Clinical trials continue to refine the PK profile, particularly in combination therapies (e.g., with venetoclax in AML).

Safety and tolerability [3]
The median duration of treatment for all patients was 36 days (range, 1–726 days), with 15 patients (15.2%) treated for > 91 days (Online Resource Table S3). The median (range) number of total daily doses received in the QW × 3, QD × 3, and QD × 5 cohorts, respectively, was 10.5 (2–72), 9.0 (6–42), and 10.0 (1–130). All 99 patients comprised the safety population; across all cohorts, 78 patients (78.8%) received ≤ 2 treatment cycles.

The MTD for QW × 3 dosing was 3200 mg (given as 1600 mg twice daily [BID]), with DLTs of nausea, thrombocytopenia, and vomiting (Online Resource Table S4), all reported at a total daily dose of 1600 mg or higher. The MTD for QD × 3 dosing was 1000 mg (given as 500 mg BID), with DLTs of thrombocytopenia, febrile neutropenia, neutropenia, and pancytopenia. For QD × 5 dosing, the MTD was 500 mg (given QD), with DLTs of thrombocytopenia, neutropenia, febrile neutropenia, and diarrhea. A total of 31 DLTs were reported across all cohorts (n = 99), with 21 patients (21.2%; dose-escalation cohorts, n = 20; apoptosis cohort, n = 1) having ≥ 1 DLT. The most common DLT was thrombocytopenia, occurring in 16 of 99 patients (16.2%). Other DLTs included neutropenia (5 [5.1%]), febrile neutropenia (3 [3.0%]), nausea (2 [2.0%]), as well as leukopenia, pancytopenia, diarrhea, and vomiting (1 each [1.0%]). Within the dose-escalation cohorts, DLTs were more common in patients on daily (40% for QD × 3 and 32.4% for QD × 5) versus weekly dosing schedules (8.3%), with a higher incidence of DLTs related to hematologic and lymphatic system disorders reported with daily regimens (Online Resource Table S4).

All 99 patients experienced ≥ 1 AE that was considered by the investigator to be related to study treatment (Table 1). The most common treatment-related AEs were diarrhea (74.7%), nausea (71.7%), vomiting (50.5%), decreased appetite (43.4%), and thrombocytopenia (39.4%; Online Resource Table S5). In general, treatment-related AEs occurred at the highest frequencies with the QD × 3 schedule; the lowest frequencies were observed with the QD × 5 schedule (Online Resource Table S5).

Grade ≥ 3 AEs of any cause occurred in 63 patients (63.6%) and were reported in higher incidences in the QD dosing regimens (Table 1). The most common grade ≥ 3 any-cause AEs were thrombocytopenia (29.3%), anemia (20.2%), neutropenia (16.2%), nausea (11.1%), and diarrhea (7.1%). Serious AEs (SAEs) were reported in 32 patients (32.3%) across all study groups (Table 1; Online Resource Table S6). Treatment-related SAEs were reported in 25 patients (25.3%); the most frequently reported (in 24 of 25 patients) were related to blood and lymphatic system disorders: thrombocytopenia/decreased platelet count (14 events), febrile neutropenia (5 events), neutropenia/decreased neutrophil count (4 events), leukopenia/decreased white blood cell count (3 events), and anemia (2 events). Treatment-related SAEs were more frequently reported with QD dosing (QD × 3, 7 of 15 [46.7%]; QD × 5, 13 of 34 [38.2%]) than QW × 3 dosing (4 of 36 [11.1%]) (Online Resource Table S6).

The majority of patients (81 of 99 [81.8%]) discontinued treatment due to non-safety reasons: disease progression (n = 77), patient consent withdrawal (n = 3), and other reason unspecified (n = 1). Eighteen patients (18.2%) withdrew due to AEs, 8 of which were considered SAEs. More AE-related discontinuations occurred in patients receiving daily dosing regimens, excluding the apoptosis imaging cohort (QD × 3, 20.0%; QD × 5, 29.4%), compared with those receiving QW × 3, excluding the food effect cohort (11.1%). The most common AEs resulting in study drug discontinuation among all patients were neutropenia, thrombocytopenia, and pulmonary embolism (3.0% each). AEs associated with study withdrawal were more likely to be hematologic in nature and grade ≥ 3 in severity.

Dose modifications/interruptions due to an AE were reported in 44 patients (44.4%) and occurred at similar frequencies with the weekly and daily schedules (Table 1). This included 16 of 36 patients (44.4%) on QW × 3 dosing, while 7 of 15 patients (46.7%) on QD × 3 dosing and 18 of 34 (52.9%) on QD × 5 dosing required dose modifications. The most frequently reported AEs leading to dose modification were thrombocytopenia (24.2%) and neutropenia (9.1%).

Overall, 7 deaths occurred during treatment or over the 28 days following the last study dose: 5 were due to progressive disease and 2 were due to an SAE (Table 1). One death (QW × 3 cohort) was due to an intra-abdominal hemorrhage and pulmonary embolism, both determined to be unrelated to study treatment. The other death (QD × 5 cohort) was due to pulmonary embolism and possibly related to study treatment.

[1]. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem. 2013 Jul 25;56(14):5979-83.

[2]. Preclinical optimization of MDM2 antagonist scheduling for cancer treatment by using a model-based approach. Clin Cancer Res. 2014, 20(14), 3742-3752.

[3]. Phase I study of daily and weekly regimens of the orally administered MDM2 antagonist idasanutlin in patients with advanced tumors. Invest New Drugs . 2021 Dec;39(6):1587-1597. https://pubmed.ncbi.nlm.nih.gov/34180037/

Idasanutlin has been used in trials studying the treatment of Neoplasms, Non-Hodgkin's Lymphoma, Leukemia, Myeloid, Acute, Recurrent Plasma Cell Myeloma, and Neoplasms, Leukemia, Acute Myeloid Leukemia.
Idasanutlin is an orally available, small molecule, antagonist of MDM2 (mouse double minute 2; Mdm2 p53 binding protein homolog), with potential antineoplastic activity. Idasanutlin binds to MDM2 blocking the interaction between the MDM2 protein and the transcriptional activation domain of the tumor suppressor protein p53. By preventing the MDM2-p53 interaction, p53 is not enzymatically degraded and the transcriptional activity of p53 is restored. This may lead to p53-mediated induction of tumor cell apoptosis. MDM2, a zinc finger nuclear phosphoprotein and negative regulator of the p53 pathway, is often overexpressed in cancer cells and has been implicated in cancer cell proliferation and survival.

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Drug Indication
Treatment of all conditions included in the category of malignant neoplasms (except nervous system, haematopoietic and lymphoid tissue)
Treatment of acute lymphoblastic leukaemia, Treatment of acute myeloid leukaemia

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Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.[1]

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Purpose: Antitumor clinical activity has been demonstrated for the MDM2 antagonist RG7112, but patient tolerability for the necessary daily dosing was poor. Here, utilizing RG7388, a second-generation nutlin with superior selectivity and potency, we determine the feasibility of intermittent dosing to guide the selection of initial phase I scheduling regimens. Experimental design: A pharmacokinetic-pharmacodynamic (PKPD) model was developed on the basis of preclinical data to determine alternative dosing schedule requirements for optimal RG7388-induced antitumor activity. This PKPD model was used to investigate the pharmacokinetics of RG7388 linked to the time-course of the antitumor effect in an osteosarcoma xenograft model in mice. These data were used to prospectively predict intermittent and continuous dosing regimens, resulting in tumor stasis in the same model system. Results: RG7388-induced apoptosis was delayed relative to drug exposure with continuous treatment not required. In initial efficacy testing, daily dosing at 30 mg/kg and twice a week dosing at 50 mg/kg of RG7388 were statistically equivalent in our tumor model. In addition, weekly dosing of 50 mg/kg was equivalent to 10 mg/kg given daily. The implementation of modeling and simulation on these data suggested several possible intermittent clinical dosing schedules. Further preclinical analyses confirmed these schedules as viable options. Conclusion: Besides chronic administration, antitumor activity can be achieved with intermittent schedules of RG7388, as predicted through modeling and simulation. These alternative regimens may potentially ameliorate tolerability issues seen with chronic administration of RG7112, while providing clinical benefit. Thus, both weekly (qw) and daily for five days (5 d on/23 off, qd) schedules were selected for RG7388 clinical testing.[2]

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Aim The oral MDM2 antagonist idasanutlin inhibits the p53-MDM2 interaction, enabling p53 activation, tumor growth inhibition, and increased survival in xenograft models. Methods We conducted a Phase I study of idasanutlin (microprecipitate bulk powder formulation) to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, food effect, and clinical activity in patients with advanced malignancies. Schedules investigated were once weekly for 3 weeks (QW × 3), once daily for 3 days (QD × 3), or QD × 5 every 28 days. We also analyzed p53 activation and the anti-proliferative effects of idasanutlin. Results The dose-escalation phase included 85 patients (QW × 3, n = 36; QD × 3, n = 15; QD × 5, n = 34). Daily MTD was 3200 mg (QW × 3), 1000 mg (QD × 3), and 500 mg (QD × 5). Most common adverse events were diarrhea, nausea/vomiting, decreased appetite, and thrombocytopenia. Dose-limiting toxicities were nausea/vomiting and myelosuppression; myelosuppression was more frequent with QD dosing and associated with pharmacokinetic exposure. Idasanutlin exposure was approximately dose proportional at low doses, but less than dose proportional at > 600 mg. Although inter-patient variability in exposure was high with all regimens, cumulative idasanutlin exposure over the whole 28-day cycle was greatest with a QD × 5 regimen. No major food effect on pharmacokinetic exposure occurred. MIC-1 levels were higher with QD dosing, increasing in an exposure-dependent manner. Best response was stable disease in 30.6% of patients, prolonged (> 600 days) in 2 patients with sarcoma. Conclusions Idasanutlin demonstrated dose- and schedule-dependent p53 activation with durable disease stabilization in some patients. Based on these findings, the QD × 5 schedule was selected for further development. [3]

C31H29CL2F2N3O4

616.48

615.15

C, 60.40; H, 4.74; Cl, 11.50; F, 6.16; N, 6.82; O, 10.38

1229705-06-9

Idasanutlin-d3-1;Idasanutlin (enantiomer)

53358942

White to off-white solid powder

1.4±0.1 g/cm3

737.3±60.0 °C at 760 mmHg

399.7±32.9 °C

0.0±2.5 mmHg at 25°C

1.623

7.09

3

8

8

42

1040

4

ClC1=C([H])C([H])=C([H])C(=C1F)[C@@]1([H])[C@]([H])(C(N([H])C2C([H])=C([H])C(C(=O)O[H])=C([H])C=2OC([H])([H])[H])=O)N([H])[C@@]([H])(C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])[C@]1(C#N)C1C([H])=C([H])C(=C([H])C=1F)Cl

TVTXCJFHQKSQQM-LJQIRTBHSA-N

InChI=1S/C31H29Cl2F2N3O4/c1-30(2,3)14-24-31(15-36,19-10-9-17(32)13-21(19)34)25(18-6-5-7-20(33)26(18)35)27(38-24)28(39)37-22-11-8-16(29(40)41)12-23(22)42-4/h5-13,24-25,27,38H,14H2,1-4H3,(H,37,39)(H,40,41)/t24-,25-,27+,31-/m0/s1

4-[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino]-3-methoxybenzoic acid

Idasanutlin; RG-7388; RO-5503781; RG 7388; RO5503781; 1229705-06-9; RG7388; RG-7388; Idasanutlin (RG-7388); Idasanutlin (RG7388); RO5503781; 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid; RG7388; RO 5503781

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 2: 5% DMSO+40% PEG 300+5% Tween 80+ddH2O: 1.25mg/mL

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Solubility in Formulation 3: 10 mg/mL (16.22 mM) in 0.5%HPMC 1%Tween80 (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)