A phase I trial of the human double minute 2 (HDM2) inhibitor MK-8242 in patients (pts) with advanced solid tumors.

Wagner, Andrew J.; Banerji, Udai; Mahipal, Amit; Somaiah, Neeta; Hirsch, Heather A.; Fancourt, Craig; Levonas, Amy; Lam, Raymond; Meister, Amy; Kemp, Ramon K.; Knox, Clayton D.; Rose, Shelonitda; Hong, David S.

doi:10.1200/jco.2015.33.15_suppl.10564

Cited by 8 publications

(16 citation statements)

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“…The pharmacokinetic analysis using whole blood specimens reported here indicates a systemic exposure of approximately 200 μM·hr for SCID mice at the 125 mg/kg dose used for testing. This systemic exposure exceeds that observed in adults with solid tumors for MK‐8242 at its MTD (400 mg) (plasma AUC 0‐12hr of 16.7 μM⋅hr) . Factoring in the blood‐to‐plasma ratio (∼0.6 in both mouse and human) and the 1.5‐ to 3‐fold higher unbound fraction in humans versus mice reduces the relevant difference between systemic exposures.…”

Section: Discussionmentioning

confidence: 82%

“…Additionally, MDM2 inhibitors commonly induce complete regression of the MDM2‐amplified ostesoarcoma line SJSA‐1 . Despite this impressive in vitro activity against liposarcoma cell lines and in vivo activity against an MDM2‐amplified xenograft, MDM2 inhibitors have shown few objective responses for patients with MDM2‐amplified liposarcoma, with response rates in the range of 5–10% . Additionally, the treatment with the MDM2 inhibitor SAR405838 appeared to rapidly select for TP53 mutations as evidenced by the appearance of TP53 mutations in circulating cell‐free DNA following initiation of treatment with SAR405838 …”

Section: Discussionmentioning

confidence: 99%

“…Using a twice‐daily schedule of administration on days 1–7 of planned 21 day treatment cycles, the maximum tolerated dose (MTD) was 400 mg for patients with solid tumors. Objective responses were noted among two of 27 liposarcoma patients treated …”

Section: Introductionmentioning

confidence: 99%

“…[20] Seven other MDM2 inhibitors have subsequently entered clinical evaluation, [15] and thrombocytopenia is a prominent toxicity at higher doses for all for which clinical data are publicly reported. [18,19,21,22] RG7112 was previously tested against the in vitro and in vivo tumor panels by the Pediatric Preclinical Testing Program (PPTP). [23] While in vitro cell line sensitivity correlated well with TP53 mutation status, there were only five objective regressions in 26 solid tumor models with wild-type TP53.…”

Section: Introductionmentioning

confidence: 99%

“…Objective responses were noted among two of 27 liposarcoma patients treated. [22] This report describes testing of MK-8242 as a single agent against the in vitro panel of PPTP as well as against the in vivo tumor panel as a single agent at its MTD. The pharmacokinetic profile of MK-8242 in treated mice is also presented to facilitate comparison of preclinical to clinical results.…”

Section: Introductionmentioning

confidence: 99%

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Initial Testing (Stage 1) of MK‐8242—A Novel MDM2 Inhibitor—by the Pediatric Preclinical Testing Program

Kang

Reynolds

Kolb

et al. 2016

Pediatric Blood & Cancer

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Background MK-8242 is an inhibitor of MDM2 that stabilizes the tumor suppressor TP53 and induces growth arrest or apoptosis downstream of TP53 induction. Procedures MK-8242 was tested against the PPTP in vitro cell line panel at concentrations from 1.0 nM to 10.0 μM and against the PPTP in vivo xenograft panels using oral gavage on Days 1–5 and Day 15–19 at a dose of 125 mg/kg (solid tumors) or 75 mg/kg [acute lymphoblastic leukemia (ALL) models]. Results The median IC50 for MK-8242 was 0.07 μM for TP53 wild-type cell lines versus > 10 μM for TP53 mutant cell lines. MK-8242 induced a two-fold or greater delay in time to event in 10 of 17 (59%) of TP53 wild-type solid tumor xenografts, excluding osteosarcoma xenografts that have very low TP53 expression. Objective responses were observed in 7 solid tumor xenografts representing multiple histotypes. For the systemic-disease ALL panel, among 8 xenografts there were 2 complete responses (CR) and 6 partial responses (PR). Two additional MLL-rearranged xenografts (MV4;11 and RS4;11) grown subcutaneously showed maintained CR and PR, respectively. The expected pharmacodynamic responses to TP53 activation were observed in TP53 wild-type models treated with MK-8242. Pharmacokinetic analysis showed that MK-8242 drug exposure in SCID mice appears to exceed that observed in adult phase 1 trials. Conclusions MK-8242 induced tumor regressions across multiple solid tumor histotypes and induced CRs or PRs for most ALL xenografts. This activity was observed at MK-8242 drug exposures that appear to exceed those observed in human phase 1 trials.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Initial Testing (Stage 1) of MK‐8242—A Novel MDM2 Inhibitor—by the Pediatric Preclinical Testing Program

Kang

Reynolds

Kolb

et al. 2016

Pediatric Blood & Cancer

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Medicinal Chemistry Strategies to Disrupt the p53–MDM2/MDMX Interaction

Lemos

Leão

Soares

et al. 2016

Medicinal Research Reviews

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The growth inhibitory activity of p53 tumor suppressor is tightly regulated by interaction with two negative regulatory proteins, murine double minute 2 (MDM2) and X (MDMX), which are overexpressed in about half of all human tumors. The elucidation of crystallographic structures of MDM2/MDMX complexes with p53 has been pivotal for the identification of several classes of inhibitors of the p53-MDM2/MDMX interaction. The present review provides in silico strategies and screening approaches used in drug discovery as well as an overview of the most relevant classes of small-molecule inhibitors of the p53-MDM2/MDMX interaction, their progress in pipeline, and highlights particularities of each class of inhibitors. Most of the progress made with high-throughput screening has led to the development of inhibitors belonging to the cis-imidazoline, piperidinone, and spiro-oxindole series. However, novel potent and selective classes of inhibitors of the p53-MDM2 interaction with promising antitumor activity are emerging. Even with the discovery of the 3D structure of complex p53-MDMX, only two small molecules were reported as selective p53-MDMX antagonists, WK298 and SJ-172550. Dual inhibition of the p53-MDM2/MDMX interaction has shown to be an alternative approach since it results in full activation of the p53-dependent pathway. The knowledge of structural requirements crucial to the development of small-molecule inhibitors of the p53-MDMs interactions has enabled the identification of novel antitumor agents with improved in vivo efficacy.

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Protein–Protein Interaction Inhibitors

Hardcastle

2017

Topics in Medicinal Chemistry

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The study of cellular mechanisms of cancer growth and survival has revealed a complex web of signalling pathways that produce the 'hallmarks of cancer'. A number of critical cellular signalling nodes have been characterised from which many new drug targets have been proposed. A number of these nodes are regulated by protein-protein interactions, and so present attractive, if challenging, targets for drug discovery. Drug discovery efforts towards three PPI families have resulted in clinically investigated drugs: i.e. Bcl-2 family inhibitors, MDM2-p53 inhibitors and IAP inhibitors. The discovery and optimisation of these drug classes are detailed in this chapter.

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A phase I trial of the human double minute 2 (HDM2) inhibitor MK-8242 in patients (pts) with advanced solid tumors.

Cited by 8 publications

References 0 publications

Initial Testing (Stage 1) of MK‐8242—A Novel MDM2 Inhibitor—by the Pediatric Preclinical Testing Program

Initial Testing (Stage 1) of MK‐8242—A Novel MDM2 Inhibitor—by the Pediatric Preclinical Testing Program

Medicinal Chemistry Strategies to Disrupt the p53–MDM2/MDMX Interaction

Protein–Protein Interaction Inhibitors

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