Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation <i>in vitro</i> and sensitize tumors to doxorubicin <i>in vivo</i>

Koblish, Holly K.; Zhao, Shuyuan; Franks, Carol F.; Donatelli, Robert R.; Tominovich, Rose; LaFrance, Louis V.; Leonard, Kristi; Gushue, Joan M.; Parks, Daniel J.; Calvo, Raul R.; Milkiewicz, Karen L.; Marugán, Juan; Raboisson, Pierre; Cummings, Maxwell D.; Grasberger, Bruce; Johnson, Dana L.; Lu, Tianbao; Molloy, Christopher J.; Maroney, Anna C.

doi:10.1158/1535-7163.mct-05-0199

Cited by 156 publications

(91 citation statements)

References 59 publications

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“…6A). Other potent MDM2 antagonists with similar binding modes and desired in vivo activities include spiro-oxindole (Ding et al 2006;Shangary et al 2008a;Shangary et al 2008b) and benzodiazepinedione analogs (Grasberger et al 2005;Koblish et al 2006) (Fig. 6B).…”

Section: Targeting the P53 Pathway: Mdm2 Mdmx Sirtuins And Beyondmentioning

confidence: 99%

The Tumor Suppressor p53: From Structures to Drug Discovery

Joerger

Fersht²

2010

Cold Spring Harbor Perspectives in Biology

299

280

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Even 30 years after its discovery, the tumor suppressor protein p53 is still somewhat of an enigma. p53's intimate and multifaceted role in the cell cycle is mirrored in its equally complex structural biology that is being unraveled only slowly. Here, we discuss key structural aspects of p53 function and its inactivation by oncogenic mutations. Concerted action of folded and intrinsically disordered domains of the highly dynamic p53 protein provides binding promiscuity and specificity, allowing p53 to process a myriad of cellular signals to maintain the integrity of the human genome. Importantly, progress in elucidating the structural biology of p53 and its partner proteins has opened various avenues for structure-guided rescue of p53 function in tumors. These emerging anticancer strategies include targeting mutant-specific lesions on the surface of destabilized cancer mutants with small molecules and selective inhibition of p53's degradative pathways.

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Section: Targeting the P53 Pathway: Mdm2 Mdmx Sirtuins And Beyondmentioning

confidence: 99%

The Tumor Suppressor p53: From Structures to Drug Discovery

Joerger

Fersht²

2010

Cold Spring Harbor Perspectives in Biology

299

280

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“…[6][7][8][9][10][11][12][13][14][15][16][17][18][19] In cells with functional p53, the p53 activity is primarily inhibited through direct and tonic interaction with the MDM2 protein. [20][21][22] Treatment of various tumor cells with inhibitors of the MDM2-p53 interaction results in rising p53 levels and subsequent induction of cell-cycle arrest and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia

Saddler¹,

Ouillette²,

Kujawski³

et al. 2008

Blood

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Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and remains incurable with conventional therapies. Patients with relapsed or resistant CLL have a significantly shortened lifespan. MDM2 inhibitors have been developed and may have significant potential in the treatment of CLL. Clinical development of these compounds would be aided through knowledge of molecular predictors of activity. To understand determinants of sensitivity or resistance to MDM2 inhibitor therapy in CLL, we comprehensively analyzed a large cohort of CLL patient-derived samples for response to MDM2 inhibition and correlated these responses with clinically important biomarkers. Furthermore, we employed high-density single nucleotide polymorphism (SNP) arrays to analyze genomewide changes of copy number and allele status, including that of p53. The results of these studies conclusively demonstrate that p53 status is the major determinant of response to MDM2 inhibitors in CLL. Additional defects in the p53 regulatory cascade do not appear operational in this leukemia. Further, we identify a novel subgroup of patients with CLL with early progressive disease that appears particularly sensitive to MDM2 inhibitor treatment. These data provide definitive evidence for target-specific and predictive activity and a rationale to proceed with this potentially important class of compounds in the treatment of CLL. IntroductionChronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the Western world, and is characterized by a highly variable clinical course. 1,2 Treatment of CLL is reserved for symptomatic patients or patients in advanced clinical stage. Despite improvements in response rates using chemoimmunotherapy combinations, CLL remains incurable, and patients refractory to fludarabine or patients who have suffered multiple disease relapses have a poor outlook. [3][4][5] Therefore, novel therapeutics are needed to advance the outlook for afflicted patients.Inhibitors of murine double minute 2 (Mdm2) represent a novel therapeutic approach. [6][7][8][9][10][11][12][13][14][15][16][17][18][19] In cells with functional p53, the p53 activity is primarily inhibited through direct and tonic interaction with the MDM2 protein. [20][21][22] Treatment of various tumor cells with inhibitors of the MDM2-p53 interaction results in rising p53 levels and subsequent induction of cell-cycle arrest and apoptosis. For poorly understood reasons, nonmalignant cells appear relatively resistant to MDM2 inhibition. 23,24 In CLL, in contrast to many solid tumors, p53 is mutated in only about 10% of patients at presentation and in 10% to 30% of patients with pretreated disease. [25][26][27][28] Thus, small-molecule inhibitors that block the MDM2-p53 interaction could represent a new therapeutic strategy for the treatment of most patients with CLL.Human cancers are biologically heterogeneous and respond nonuniformly to therapeutic intervention. Therefore, understanding the molecular mechanisms underlying cancer susceptibili...

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“…Several compounds have been identified that prevent the association between p53 and Mdm2 (Nutlin3 and Rita; refs. [7][8][9]. In addition, compounds that target the ubiquitin ligase domain of Mdm2 can also protect or engage p53 activity (10).…”

Section: Introductionmentioning

confidence: 99%