Discovery of a novel class of highly potent inhibitors of the p53–MDM2 interaction by structure-based design starting from a conformational argument

Furet, Pascal; Masuya, Keiichi; Kallen, Joerg; Stachyra, Therese‐Marie; Ruetz, Stephan; Guagnano, Vito; Holzer, Philipp; Mah, Robert; Stutz, Stefan; Vaupel, Andrea; Chêne, Patrick; Jeay, Sébastien; Schlapbach, Achim

doi:10.1016/j.bmcl.2016.08.010

Cited by 60 publications

(40 citation statements)

References 15 publications

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“…HDM201 from Novartis is an imidazopyrrolidinone scaffold-based inhibitor of the P53-MDM2 protein–protein interaction with superior characteristics in terms of in vitro activity/selectivity and of in vivo features of oral bioavailability, pharmacokinetic, and pharmacodynamic profiles as assessed in animals [117, 118]. In particular, the optimized interactions of HDM201 with MDM2 protein are responsible for the increased stabilization of the complex leading to a higher potency of the molecule [119].…”

Section: Introductionmentioning

confidence: 99%

MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer

et al. 2017

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The two murine double minute (MDM) family members MDM2 and MDMX are at the center of an intense clinical assessment as molecular target for the management of cancer. Indeed, the two proteins act as regulators of P53, a well-known key controller of the cell cycle regulation and cell proliferation that, when altered, plays a direct role on cancer development and progression. Several evidence demonstrated that functional aberrations of P53 in tumors are in most cases the consequence of alterations on the MDM2 and MDMX regulatory proteins, in particular in patients with hematological malignancies where TP53 shows a relatively low frequency of mutation while MDM2 and MDMX are frequently found amplified/overexpressed. The pharmacological targeting of these two P53-regulators in order to restore or increase P53 expression and activity represents therefore a strategy for cancer therapy. From the discovery of the Nutlins in 2004, several compounds have been developed and reported with the ability of targeting the P53-MDM2/X axis by inhibiting MDM2 and/or MDMX. From natural compounds up to small molecules and stapled peptides, these MDM2/X pharmacological inhibitors have been extensively studied, revealing different biological features and different rate of efficacy when tested in in vitro and in vivo experimental tumor models. The data/evidence coming from the preclinical experimentation have allowed the identification of the most promising molecules and the setting of clinical studies for their evaluation as monotherapy or in therapeutic combination with conventional chemotherapy or with innovative therapeutic protocols in different tumor settings. Preliminary results have been recently published reporting data about safety, tolerability, potential side effects, and efficacy of such therapeutic approaches. In this light, the aim of this review is to give an updated overview about the state of the art of the clinical evaluation of MDM2/X inhibitor compounds with a special attention to hematological malignancies and to the potential for the management of pediatric cancers.

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Section: Introductionmentioning

confidence: 99%

MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer

et al. 2017

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“…ARF loss raises the MDM2 level, which in turn degrades TP53. HDM201 disrupts both human and murine TP53-MDM2 interactions, with nanomolar cellular IC 50 values, blocking TP53 degradation (11,12). Because of Arf deletion, we expected RosaPB/+;ATP2/+;Arf −/− transplanted tumors to respond to HDM201; however, the insertional landscapes may alter the dependency by introducing other, eventually dominant, oncogenic events (Fig.…”

Section: Pb-induced Spontaneous Tumors In the Arfmentioning

confidence: 99%

“…In this study, we sought to understand which genes might function as key drivers of resistance to MDM2-TP53 inhibition. We chose to study resistance to HDM201, a highly specific, murine-compatible, and potent small-molecule inhibitor of the TP53-MDM2 protein-protein interaction (9,11), which is structurally similar to a new class of inhibitors based on an imidazopyrrolidinone scaffold (12). HDM201 has recently entered Phase 1 clinical trials in cancer patients.…”

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confidence: 99%

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Chapeau

Gembarska

Durand

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Inhibitors of double minute 2 protein (MDM2)-tumor protein 53 (TP53) interaction are predicted to be effective in tumors in which the TP53 gene is wild type, by preventing TP53 protein degradation. One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor. Here we used piggyBac (PB) transposon insertional mutagenesis to anticipate resistance mechanisms occurring during treatment with the MDM2-TP53 inhibitor HDM201. Constitutive PB mutagenesis in Arf −/− mice provided a collection of spontaneous tumors with characterized insertional genetic landscapes. Tumors were allografted in large cohorts of mice to assess the pharmacologic effects of HDM201. Sixteen out of 21 allograft models were sensitive to HDM201 but ultimately relapsed under treatment. A comparison of tumors with acquired resistance to HDM201 and untreated tumors identified 87 genes that were differentially and significantly targeted by the PB transposon. Resistant tumors displayed a complex clonality pattern suggesting the emergence of several resistant subclones. Among the most frequent alterations conferring resistance, we observed somatic and insertional loss-of-function mutations in transformation-related protein 53 (Trp53) in 54% of tumors and transposonmediated gain-of-function alterations in B-cell lymphoma-extra large (Bcl-xL), Mdm4, and two TP53 family members, resulting in expression of the TP53 dominant negative truncations ΔNTrp63 and ΔNTrp73. Enhanced BCL-xL and MDM4 protein expression was confirmed in resistant tumors, as well as in HDM201-resistant patient-derived tumor xenografts. Interestingly, concomitant inhibition of MDM2 and BCL-xL demonstrated significant synergy in p53 wild-type cell lines in vitro. Collectively, our findings identify several potential mechanisms by which TP53 wild-type tumors may escape MDM2-targeted therapy.drug resistance | MDM2 inhibitor | piggyBac screen | cancer A mong the genes most commonly altered in human cancer, regardless of tumor type, are tumor protein 53 (TP53) tumor suppressor (1) and CDKN2A (INK4a/ARF) (2). The latter gene encodes two tumor suppressor proteins: p16INK4a (3), an inhibitor of cyclin D-dependent kinases that, at least in part, regulates the function of the retinoblastoma protein (RB), and p19ARF (4), a negative regulator of double minute 2 protein (MDM2) function that activates TP53, thereby inducing cell cycle arrest or apoptosis. TP53 protein levels are regulated through MDM2-mediated degradation.Toward the goal of reactivating TP53 in cells harboring inactivating upstream pathway alterations, compounds inhibiting the interaction between MDM2 and TP53, preventing TP53 degradation, have been discovered. Such agents induce TP53 reactivation in tumors in which the TP53 gene is wild type (5-8).Although preclinical studies of such MDM2 inhibitors have demonstrated significant antitumor activity, tumors commonly relapse (9, 10).Rapid emergence of resistance is...

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“…Analysis of patient tumors by intersecting high-throughput cell line sensitivity data with genomic data from the ongoing trial has identified distinct p53 target genes that predict sensitivity to NVP-CGM097, a genetic signature that can be used for selection of patients that would be most sensitive to treatment with NVP-CGM097 or other MDM2 antagonists (Jeay et al, 2015). The Novartis laboratories have also designed a new MDM2 inhibitor with a pyrazolopyrrolidinone core based on MDM2's structure when bound to dihydroisoquinolinones and have discovered HDM201 (Furet et al, 2016), which has likewise entered phase I clinical trials for tumors with wild-type p53 (NCT02143635), for liposarcomas in combination with LEE011 (also known as Ribociclib), a novel CDK4/6 inhibitor (Infante et al, 2016) (NCT02343172), and as part of a personalized neuroblastoma clinical trial that will apply next generation sequencing on biopsies of patient tumors, followed by treatment with either trametinib, certinib (an ALK inhibitor) (Shaw et al, 2014), or HDM201, depending on the deep sequencing results (NCT02780128). Another lead small molecule developed with support from Merck and whose structure has not been disclosed is MK-8242 (Kang et al, 2016), which has demonstrated efficacy in the Pediatric Preclinical Testing Program (PPTP) (Houghton et al, 2007), an established panel of childhood cancer xenografts and cell lines used to test novel therapeutic agents, and has entered phase I clinical trials for AML (Ravandi et al, 2016) (NCT01451437) and advanced solid tumors (NCT01463696).…”

Section: Small Molecule Wild-type P53 Activatorsmentioning

confidence: 99%

Reviving the guardian of the genome: Small molecule activators of p53

Nguyen

Liao

Zeng

et al. 2017

Pharmacology & Therapeutics

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The tumor suppressor p53 is one of the most important proteins for protection of genomic stability and cancer prevention. Cancers often inactivate it by either mutating its gene or disabling its function. Thus, activating p53 becomes an attractive approach for the development of molecule-based anti-cancer therapy. The past decade and half have witnessed tremendous progress in this area. This essay offers readers with a grand review on this progress with updated information about small molecule activators of p53 either still at bench work or in clinical trials.

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Discovery of a novel class of highly potent inhibitors of the p53–MDM2 interaction by structure-based design starting from a conformational argument

Cited by 60 publications

References 15 publications

MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer

MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Reviving the guardian of the genome: Small molecule activators of p53

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Discovery of a novel class of highly potent inhibitors of the p53–MDM2 interaction by structure-based design starting from a conformational argument

Cited by 60 publications

References 15 publications

MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer

MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf −/− mouse model

Reviving the guardian of the genome: Small molecule activators of p53

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Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model