LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

Cs, Hong; Ho, W.; Zhang, C; Yang, Chunzhang; Jb, Elder; Zhuang, Zhengping

doi:10.1080/15384047.2015.1040961

Cited by 91 publications

(117 citation statements)

References 151 publications

(158 reference statements)

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“…Given the many preclinical in vivo studies indicating that inhibition of PP2A by LB-100 enhances the antiproliferative activity of a variety of standard anticancer agents by apparently several mechanisms without significantly enhancing their toxicity (20), we sought to determine the MTD of LB-100 given daily for 3 consecutive days in patients with refractory solid tumors as a first step in developing combination regimens of this PP2A inhibitor with a cytotoxic drug and/or radiation.…”

Section: Introductionmentioning

confidence: 99%

Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial

Chung

Mansfield

Braiteh

et al. 2017

Clinical Cancer Research

102

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Purpose: To determine the MTD and to assess the safety, tolerability, and potential activity of LB-100, a first-in-class small-molecule inhibitor of protein phosphatase 2A (PP2A) in adult patients with progressive solid tumors.Experimental Design: LB-100 was administered intravenously daily for 3 days in 21-day cycles in a 3 þ 3 dose escalation design.Results: There were 29 patient entries over 7 dose escalations. One patient stopped treatment after one dose because of an acute infection and was reenrolled after recovery; each course was analyzed as a separate patient entry. Two patients had doselimiting toxicity (reversible increases in serum creatinine or calculated serum creatinine clearance) at the 3

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Section: Introductionmentioning

confidence: 99%

Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial

Chung

Mansfield

Braiteh

et al. 2017

Clinical Cancer Research

102

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“…Exploiting molecularly specific pharmacologic interventions has achieved eradication in a broad range of cancers. Preclinical studies have shown that the inhibition of PP2A by a novel small molecule compound, LB100, enhances the antineoplastic activity of a variety of rationally designed anticancer agents via multiple mechanisms without significantly enhancing their toxicity [33]. To the best of our knowledge, this is the first report to demonstrate PP2A inhibition as a new therapeutic approach to enhancing the efficacy of cisplatin against mucoepidermoid carcinoma salivary gland tumors.…”

Section: Discussionmentioning

confidence: 82%

Inhibition of Protein Phosphatase 2A Sensitizes Mucoepidermoid Carcinoma to Chemotherapy via the PI3K-AKT Pathway in Response to Insulin Stimulus

Liu¹,

Wang²,

Cui³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Protein phosphatase 2A (PP2A) is a ubiquitous serine/threonine phosphatase that mediates cell cycle regulation and metabolism. Mounting evidence has indicated that PP2A inhibition exhibits considerable anticancer potency in multiple types of human cancers. However, the efficacy of PP2A inhibition remains unexplored in mucoepidermoid carcinoma (MEC), especially in locally advanced and metastatic cases with limited systemic treatment. In this study, we demonstrated the therapeutic potency of LB100 in mucoepidermoid carcinoma. Methods: In this study, the expression of PP2A was evaluated using immunohistochemical (IHC) staining. The effects associated with LB100 alone and in combination with cisplatin for the treatment of mucoepidermoid carcinoma were investigated both in vitro, regarding metabolism, proliferation, and migration, and in vivo in a mucoepidermoid carcinoma xenograft model. In addition, with LB100 treatment and in response to an insulin stimulus, the expression levels and phosphorylation levels of targets in the PI3K-AKT pathway were determined using western blot analysis and immunoblotting. Results: The expression of protein phosphatase 2A was significantly upregulated in the clinical specimens of high-grade MECs compared with those of low-/medium-grade MECs and normal controls. In this article, we report that a small molecule PP2A inhibitor, LB100, decreased cellular viability and glycolytic activity and induced G2/M cell cycle arrest. Importantly, LB100 enhanced the efficacy of cisplatin in mucoepidermoid carcinoma cells both in vitro and in vivo. PP2A inhibition by LB100 increased the phosphorylation of insulin receptor substrate 1(IRS-1) on serine residues, downregulated the expression of phosphatidylinositol 3-kinase (PI3K) p110 alpha subunit and dephosphorylated AKT at Ser473 and Thr308 in mucoepidermoid carcinoma cells in response to insulin stimulus. Conclusion: These results highlight the translational potential of PP2A inhibition to synergize with cisplatin in mucoepidermoid carcinoma treatment.

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“…In preclinical studies, LB-100 was shown to inhibit proliferation and induce apoptosis in a variety of cultured cancer cells. LB-100 also acts as an effective chemo-and radiosensitizer for the treatment of various cancers, and LB-100 exhibited potent in vivo antineoplastic activity in combination with cisplatin or doxorubicin in mouse xenograft models (21,23,25,27,80,81). The first-in-human phase I trial (NCT01837667) recently concluded that the safety, tolerability, and preliminary evidence of antitumor activity support the continued development of LB-100 Figure 3.…”

Section: Discussionmentioning

confidence: 99%

“…In nearly all reports describing LB-100 activity, the target of LB-100 is ascribed to the specific inhibition of ser/thr protein phosphatase type 2A (PP2A; refs. 21,23,25,27,80,81). However, the most cited reference to support selectivity for PP2A (22) was corrected in 2009, revealing that the compound with >10,000-fold selectivity for PP2A was another endothall derivative [LB-102; 4-(3-carboxy-7-oxa-bicyclo [2.2.1] heptane-2-carbonyl)piperazine-1-carboxylic acid tert-butyl ester; Fig.…”

Section: Discussionmentioning

confidence: 99%

The Antitumor Drug LB-100 Is a Catalytic Inhibitor of Protein Phosphatase 2A (PPP2CA) and 5 (PPP5C) Coordinating with the Active-Site Catalytic Metals in PPP5C

D’Arcy

Swingle

Papke

et al. 2019

Molecular Cancer Therapeutics

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LB-100 is an experimental cancer therapeutic with cytotoxic activity against cancer cells in culture and antitumor activity in animals. The first phase I trial (NCT01837667) evaluating LB-100 recently concluded that safety and efficacy parameters are favorable for further clinical testing. Although LB-100 is widely reported as a specific inhibitor of serine/ threonine phosphatase 2A (PP2AC/PPP2CA:PPP2CB), we could find no experimental evidence in the published literature demonstrating the specific engagement of LB-100 with PP2A in vitro, in cultured cells, or in animals. Rather, the premise for LB-100 targeting PP2AC is derived from studies that measure phosphate released from a phosphopeptide (K-R-pT-I-R-R) or inferred from the ability of LB-100 to mimic activity previously reported to result from the inhibition of PP2AC by other means. PP2AC and PPP5C share a common catalytic mechanism. Here, we demonstrate that the phosphopeptide used to ascribe LB-100 specificity for PP2A is also a substrate for PPP5C. Inhibition assays using purified enzymes demonstrate that LB-100 is a catalytic inhibitor of both PP2AC and PPP5C. The structure of PPP5C cocrystallized with LB-100 was solved to a resolution of 1.65Å, revealing that the 7-oxabicyclo[2.2.1]heptane-2,3-dicarbonyl moiety coordinates with the metal ions and key residues that are conserved in both PP2AC and PPP5C. Cell-based studies revealed some known actions of LB-100 are mimicked by the genetic disruption of PPP5C. These data demonstrate that LB-100 is a catalytic inhibitor of both PP2AC and PPP5C and suggest that the observed antitumor activity might be due to an additive effect achieved by suppressing both PP2A and PPP5C.

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LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

Cited by 91 publications

References 151 publications

Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial

Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial

Inhibition of Protein Phosphatase 2A Sensitizes Mucoepidermoid Carcinoma to Chemotherapy via the PI3K-AKT Pathway in Response to Insulin Stimulus

The Antitumor Drug LB-100 Is a Catalytic Inhibitor of Protein Phosphatase 2A (PPP2CA) and 5 (PPP5C) Coordinating with the Active-Site Catalytic Metals in PPP5C

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