Structure-Based Design of Novel Inhibitors of the MDM2–p53 Interaction

Rew, Yosup; Sun, Daqing; Turiso, Felix González-López de; Bartberger, Michael D.; Beck, Hilary P.; Canon, Jude; Chen, Ada; Chow, David; Deignan, Jeffrey; Fox, Brian M.; Gustin, Darin J.; Huang, Xin; Jiang, Min; Jiao, Xiaojin; Jin, Lixia; Kayser, Frank; Kopecky, David J.; Li, Yihong; Lo, Mei-Chu; Long, Alexander; Michelsen, Klaus; Oliner, Jonathan D.; Osgood, Tao; Ragains, Mark L.; Saiki, Anne Y.; Schneider, Steve; Toteva, Maria M.; Yakowec, P.; Yan, Xuelei; Ye, Qiuping; Yu, Dongyin; Zhao, Xiaoning; Zhou, Jing; Medina, Julio C.; Olson, Steven H.

doi:10.1021/jm300354j

Cited by 150 publications

(158 citation statements)

References 21 publications

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“…AMG 232 potently inhibits the MDM2-p53 interaction AMG 232 was discovered via optimization of AM-8553, our previously described piperidinone inhibitor of MDM2 (10). Further investigation into the N-alkyl substituent of this series led to the discovery of AMG 232 ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Inhibition of the MDM2-p53 protein-protein interaction would block each of these mechanisms and is, therefore, an attractive target for restoration of p53 activity in tumor cells. Preclinical studies have indeed demonstrated restoration of p53 activity and inhibition of tumor growth by small-molecule MDM2 inhibitors (7)(8)(9)(10)(11). Previously, we reported the de novo design of AM-8553 as a potent and selective piperidinone inhibitor of the MDM2-p53 interaction (10).…”

Section: Introductionmentioning

confidence: 96%

“…Preclinical studies have indeed demonstrated restoration of p53 activity and inhibition of tumor growth by small-molecule MDM2 inhibitors (7)(8)(9)(10)(11). Previously, we reported the de novo design of AM-8553 as a potent and selective piperidinone inhibitor of the MDM2-p53 interaction (10). Further research led to the discovery of AMG 232, which has excellent in vivo properties and is the most potent MDM2 inhibitor described to date (12).…”

Section: Introductionmentioning

confidence: 97%

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The MDM2 Inhibitor AMG 232 Demonstrates Robust Antitumor Efficacy and Potentiates the Activity of p53-Inducing Cytotoxic Agents

Canon

Osgood

Olson

et al. 2015

Molecular Cancer Therapeutics

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Abstractp53 is a critical tumor suppressor and is the most frequently inactivated gene in human cancer. Inhibition of the interaction of p53 with its negative regulator MDM2 represents a promising clinical strategy to treat p53 wild-type tumors. AMG 232 is a potential best-in-class inhibitor of the MDM2-p53 interaction and is currently in clinical trials. We characterized the activity of AMG 232 and its effect on p53 signaling in several preclinical tumor models. AMG 232 binds the MDM2 protein with picomolar affinity and robustly induces p53 activity, leading to cell-cycle arrest and inhibition of tumor cell proliferation. AMG 232 treatment inhibited the in vivo growth of several tumor xenografts and led to complete and durable regression of MDM2-amplified SJSA-1 tumors via growth arrest and induction of apoptosis. Therapeutic combination studies of AMG 232 with chemotherapies that induce DNA damage and p53 activity resulted in significantly superior antitumor efficacy and regression, and markedly increased activation of p53 signaling in tumors. These preclinical data support the further evaluation of AMG 232 in clinical trials as both a monotherapy and in combination with standard-of-care cytotoxics.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 97%

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The MDM2 Inhibitor AMG 232 Demonstrates Robust Antitumor Efficacy and Potentiates the Activity of p53-Inducing Cytotoxic Agents

Canon

Osgood

Olson

et al. 2015

Molecular Cancer Therapeutics

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119

114

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“…After optimization of Nutlin-3a, RG-7112 was the fi rst Mdm2 inhibitor used in clinical trials to treat multiple human cancers ). Other companies like Amgen developed a series of optimized compounds from the piperidinone class of compounds, obtaining AM -8553 that effi ciently inhibits tumour regression (Rew et al 2012 ). Since 2013, Amgen also developed the Mdm2 inhibitor, AMG -8735 , containing a morpholinone core with a signifi cant increase in both potency and metabolic stability compared to the piperidinone series.…”

Section: Inhibitors Of P53/mdm2mentioning

confidence: 99%

The Ubiquitin-Proteasome System (UPS) as a Cancer Drug Target: Emerging Mechanisms and Therapeutics

Mata-Cantero

Lobato-Gil²,

Aillet³

et al. 2014

Stress Response Pathways in Cancer

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The Ubiquitin-Proteasome System (UPS) plays an important role in the setting of the cellular response to multiple stress signals. Although the primary function of ubiquitin was initially associated with proteolysis, it is now considered as a key regulator of protein function controlling, among other functions, signalling cascades, transcription, apoptosis or oncogenesis. Failure at any level of the UPS is associated with the development of multiple pathologies including metabolic problems, immune diseases, infl ammation and cancer. The successful use of the proteasome inhibitor Bortezomib (Velcade) in the treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL) revealed the potential of the UPS as pharmacological target. Ten years later, new inhibitors tackling not only the proteasome but also different subsets of enzymes which conjugate or de-conjugate ubiquitin or ubiquitin-like molecules, have been developed. Most of them are excellent tools to characterize better the emerging molecular mechanisms regulating distinct critical cellular processes. Some of them have been launched already while many others are still in pre-clinical development. This chapter updates some of the most successful efforts to develop and characterize inhibitors of the UPS which tackle mechanisms involved in cancer. Particular attention has been dedicated to updating the status of the clinical trials of these inhibitors.

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“…The high potency of 1 can be rationalized by the cocrystal structure of 1 bound to MDM2. 15 Compound 1 occupies the three critical binding pockets of Leu26 (p53) , Trp23 (p53) , and Phe19 (p53) . The C5 aryl group reaches deep into the Leu26 (p53 ) pocket and engages in a face-to-face π-stacking interaction with H96, while the C6 aryl group fills the Trp23 (p53) binding cavity.…”

mentioning

confidence: 99%

Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2–p53 Interaction

Yu¹,

Wang²,

Zhu³

et al. 2014

ACS Med. Chem. Lett.

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Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone−pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Compound 23 exhibits excellent pharmacokinetic properties and substantial in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft mouse model. KEYWORDS: MDM2, p53, protein−protein interaction, piperidinone, pyridine P rotein p53 has been recognized as the "guardian of the genome" and is a main cell tumor suppressor. 1 It induces the cell growth arrest and apoptosis in response to DNA damage or stress. 2,3 In about 50% of human cancers, p53 is mutated or deleted resulting in loss of it functions. The wildtype p53 in the remaining 50% of malignancies is regulated by human murine double minute 2 (MDM2) oncoprotein 4,5 through three main mechanisms. First, MDM2 directly binds to and blocks the N-terminal transcriptional activation domain of p53. Second, MDM2 promotes export of p53 from the nucleus to the cytoplasm. Finally, MDM2 induces degradation of p53 via ubiquitination through its E3 ligase activity. 6 Since these mechanisms can be blocked by neutralizing the MDM2−p53 interaction, disrupting this interaction has emerged as a promising strategy to reactivate the p53 pathway. 7 To date, studies with small molecule MDM2 inhibitors have demonstrated complete tumor regression in vivo. 8−10 Several of these molecules have been tested in the clinic for the treatment of cancer. 11−14 We previously reported the discovery of AM-8553 (1) 15 (Figure 1) as a potent and selective inhibitor of the MDM2− p53 interaction. Compound 1 substantially inhibited the MDM2−p53 interaction in the biochemical HTRF binding assay (IC 50 = 1.1 nM) and the growth of human SJSA-1 tumor cell lines in the EdU cell proliferation assay (IC 50 = 0.073 μM); 16 however, it suffered a high clearance (CL = 3.5 L/h/kg) and poor bioavailability (%F = 12) in mouse. The high potency of 1 can be rationalized by the cocrystal structure of 1 bound to MDM2. 15 Compound 1 occupies the three critical binding pockets of Leu26 (p53) , Trp23 (p53) , and Phe19 (p53) . The C5 aryl group reaches deep into the Leu26 (p53 ) pocket and engages in a face-to-face π-stacking interaction with H96, while the C6 aryl group fills the Trp23 (p53) binding cavity. The ethyl group is directed into the Phe19 (p53) pocket by the conformational

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Structure-Based Design of Novel Inhibitors of the MDM2–p53 Interaction

Cited by 150 publications

References 21 publications

The MDM2 Inhibitor AMG 232 Demonstrates Robust Antitumor Efficacy and Potentiates the Activity of p53-Inducing Cytotoxic Agents

The MDM2 Inhibitor AMG 232 Demonstrates Robust Antitumor Efficacy and Potentiates the Activity of p53-Inducing Cytotoxic Agents

The Ubiquitin-Proteasome System (UPS) as a Cancer Drug Target: Emerging Mechanisms and Therapeutics

Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2–p53 Interaction

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