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author:("feret, Pascal")
1.  A distinct p53 target gene set predicts for response to the selective p53–HDM2 inhibitor NVP-CGM097 
eLife  null;4:e06498.
Biomarkers for patient selection are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report the discovery of a novel patient selection strategy for the p53–HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By intersecting high-throughput cell line sensitivity data with genomic data, we have identified a gene expression signature consisting of 13 up-regulated genes that predicts for sensitivity to NVP-CGM097 in both cell lines and in patient-derived tumor xenograft models. Interestingly, these 13 genes are known p53 downstream target genes, suggesting that the identified gene signature reflects the presence of at least a partially activated p53 pathway in NVP-CGM097-sensitive tumors. Together, our findings provide evidence for the use of this newly identified predictive gene signature to refine the selection of patients with wild-type p53 tumors and increase the likelihood of response to treatment with p53–HDM2 inhibitors, such as NVP-CGM097.
eLife digest
Stress from daily activities and exposure to chemicals or UV radiation can all damage cells. Damaged cells may develop into cancerous tumors if unchecked. Normally, a protein called p53 helps to repair or eliminate damaged cells and prevent tumors from forming. The p53 protein does this by switching on or off genes that control DNA repair, cell division, and cell death. But half of all cancerous tumors have mutations that prevent p53 from doing its job.
Another protein called HDM2 keeps p53 in check by binding to p53 and preventing it from switching on and off genes after the stress passes. In cancers that have normal p53, sometimes HDM2 is overly active and prevents p53 from suppressing tumor formation and growth. Scientists are developing anticancer drugs that work by targeting HDM2; this frees p53 and allows it to wipe out cancerous cells. However, it is not always clear which patients with cancer are the most likely to benefit from anti-HDM2 therapy.
Jeay et al. screened hundreds of cancer cells to determine which ones are sensitive to HDM2-targeting drugs. As expected, the screen revealed that cancer cells that have mutations in the gene encoding p53 are insensitive to the anti-HDM2 drug because there is no working p53 to free up. But about 60% of the cancer cells that have normal p53 proteins also did not respond to the anti-HDM2 therapy. This finding indicates that the presence of normal p53 protein is necessary but not sufficient for tumor cells to respond to anti-HDM2 therapy.
Next, Jeay et al. compared the patterns of gene expression in the cancer cells that responded to an anti-HDM2 drug with those in cells that didn't respond. The analysis showed that a group of 13 genes are expressed more in the cells that responded to the drug. All 13 genes are unexpectedly direct targets of p53, suggesting that p53 remains active in these tumor cells, even if it is not working optimally. To verify these results, Jeay et al. grew human tumors in mice and found that tumors with high expression of the 13 genes are sensitive to the anti-HDM2 drug (called NVP-CGM097). The experiments strongly suggest that this 13-gene signature can be used to determine if a patient with cancer will respond to anti-HDM2 therapy. Following on from this work, researchers have already launched an early clinical trial with the anti-HDM2 drug and will test whether this gene signature is indeed useful in a real clinical setting.
PMCID: PMC4468608  PMID: 25965177
translational oncology; predictive signature; p53; HDM2; human
2.  Antileukemic Effects of Novel First- and Second-Generation FLT3 Inhibitors 
Genes & Cancer  2010;1(10):1021-1032.
Constitutively activated mutant FLT3 has emerged as a promising target for therapy for the subpopulation of acute myeloid leukemia (AML) patients who harbor it. The small molecule inhibitor, PKC412, targets mutant FLT3 and is currently in late-stage clinical trials. However, the identification of PKC412-resistant leukemic blast cells in the bone marrow of AML patients has propelled the development of novel and structurally distinct FLT3 inhibitors that have the potential to override drug resistance and more efficiently prevent disease progression or recurrence. Here, we present the novel first-generation “type II” FLT3 inhibitors, AFG206, AFG210, and AHL196, and the second-generation “type II” derivatives and AST487 analogs, AUZ454 and ATH686. All agents potently and selectively target mutant FLT3 protein kinase activity and inhibit the proliferation of cells harboring FLT3 mutants via induction of apoptosis and cell cycle inhibition. Cross-resistance between “type I” inhibitors, PKC412 and AAE871, was demonstrated. While cross-resistance was also observed between “type I” and first-generation “type II” FLT3 inhibitors, the high potency of the second-generation “type II” inhibitors was sufficient to potently kill “type I” inhibitor-resistant mutant FLT3-expressing cells. The increased potency observed for the second-generation “type II” inhibitors was observed to be due to an improved interaction with the ATP pocket of FLT3, specifically associated with introduction of a piperazine moiety and placement of an amino group in position 2 of the pyrimidine ring. Thus, we present 2 structurally novel classes of FLT3 inhibitors characterized by high selectivity and potency toward mutant FLT3 as a molecular target. In addition, presentation of the antileukemic effects of “type II” inhibitors, such as AUZ454 and ATH686, highlights a new class of highly potent FLT3 inhibitors able to override drug resistance that less potent “type I” inhibitors and “type II” first-generation FLT3 inhibitors cannot.
PMCID: PMC3092267  PMID: 21779428
neoplasia; FLT3 inhibitor; AML; leukemia; structure affinity; drug resistance; drug potency
3.  The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis 
Angiogenesis  2010;13(3):259-267.
EphB4 and its cognitive ligand ephrinB2 play an important role in embryonic vessel development and vascular remodeling. In addition, several reports suggest that this receptor ligand pair is also involved in pathologic vessel formation in adults including tumor angiogenesis. Eph/ephrin signaling is a complex phenomena characterized by receptor forward signaling through the tyrosine kinase of the receptor and ephrin reverse signaling through various protein–protein interaction domains and phosphorylation motifs of the ephrin ligands. Therefore, interfering with EphR/ephrin signaling by the means of targeted gene ablation, soluble receptors, dominant negative mutants or antisense molecules often does not allow to discriminate between inhibition of Eph/ephrin forward and reverse signaling. We developed a specific small molecular weight kinase inhibitor of the EphB4 kinase, NVP-BHG712, which inhibits EphB4 kinase activity in the low nanomolar range in cellular assays showed high selectivity for targeting the EphB4 kinase when profiled against other kinases in biochemical as well as in cell based assays. Furthermore, NVP-BHG712 shows excellent pharmacokinetic properties and potently inhibits EphB4 autophosphorylation in tissues after oral administration. In vivo, NVP-BHG712 inhibits VEGF driven vessel formation, while it has only little effects on VEGF receptor (VEGFR) activity in vitro or in cellular assays. The data shown here suggest a close cross talk between the VEGFR and EphR signaling during vessel formation. In addition to its established function in vascular remodeling and endothelial arterio-venous differentiation, EphB4 forward signaling appears to be an important mediator of VEGF induced angiogenesis since inhibition of EphB4 forward signaling is sufficient to inhibit VEGF induced angiogenesis.
PMCID: PMC2941628  PMID: 20803239
Angiogenesis; EphB4; EphrinB2; VEGF; Protein kinase inhibitor
4.  Catalytic inhibition of topoisomerase II by a novel rationally designed ATP-competitive purine analogue 
Topoisomerase II poisons are in clinical use as anti-cancer therapy for decades and work by stabilizing the enzyme-induced DNA breaks. In contrast, catalytic inhibitors block the enzyme before DNA scission. Although several catalytic inhibitors of topoisomerase II have been described, preclinical concepts for exploiting their anti-proliferative activity based on molecular characteristics of the tumor cell have only recently started to emerge. Topoisomerase II is an ATPase and uses the energy derived from ATP hydrolysis to orchestrate the movement of the DNA double strands along the enzyme. Thus, interfering with ATPase function with low molecular weight inhibitors that target the nucleotide binding pocket should profoundly affect cells that are committed to undergo mitosis.
Here we describe the discovery and characterization of a novel purine diamine analogue as a potent ATP-competitive catalytic inhibitor of topoisomerase II. Quinoline aminopurine compound 1 (QAP 1) inhibited topoisomerase II ATPase activity and decatenation reaction at sub-micromolar concentrations, targeted both topoisomerase II alpha and beta in cell free assays and, using a quantitative cell-based assay and a chromosome segregation assay, displayed catalytic enzyme inhibition in cells. In agreement with recent hypothesis, we show that BRCA1 mutant breast cancer cells have increased sensitivity to QAP 1.
The results obtained with QAP 1 demonstrate that potent and selective catalytic inhibition of human topoisomerase II function with an ATP-competitive inhibitor is feasible. Our data suggest that further drug discovery efforts on ATP-competitive catalytic inhibitors are warranted and that such drugs could potentially be developed as anti-cancer therapy for tumors that bear the appropriate combination of molecular alterations.
PMCID: PMC2628638  PMID: 19128485
5.  Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia 
A case study showing how the determination of multiple cocrystal structures of the protein tyrosine kinase c-Abl was used to support drug discovery, resulting in a compound effective in the treatment of chronic myelogenous leukaemia.
Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which has a constitutively activated Abl tyrosine kinase domain. Although most chronic phase CML patients treated with imatinib as first-line therapy maintain excellent durable responses, patients who have progressed to advanced-stage CML frequently fail to respond or lose their response to therapy owing to the emergence of drug-resistant mutants of the protein. More than 40 such point mutations have been observed in imatinib-resistant patients. The crystal structures of wild-type and mutant Abl kinase in complex with imatinib and other small-molecule Abl inhibitors were determined, with the aim of understanding the molecular basis of resistance and to aid in the design and optimization of inhibitors active against the resistance mutants. These results are presented in a way which illustrates the approaches used to generate multiple structures, the type of information that can be gained and the way that this information is used to support drug discovery.
PMCID: PMC2483489  PMID: 17164530
tyrosine kinase; drug discovery; imatinib; nilotinib

Results 1-5 (5)