The CDC25 phosphatases are key regulators of cell cycle progression and play a central role in th... more The CDC25 phosphatases are key regulators of cell cycle progression and play a central role in the checkpoint response to DNA damage. Their inhibition may therefore represent a promising therapeutic approach in oncology, and small molecule design strategies are currently leading to the identification of various classes of CDC25 inhibitors. Most structures developed so far are quinonoid-based compounds, but also phosphate surrogates or electrophilic entities. Considering the characteristics of the highly conserved active sites of the enzymes, many mechanisms of action have been proposed for these inhibitors. Quinonoid compounds may oxidize the catalytic site cysteine, but can also be considered as Michaël acceptors capable of reacting with the activated thiolate or other electrophilic entities. Phosphate surrogates are thought to interfere with the arginine residue, leading to reversible enzyme inhibition. But some inhibitors can combine in the same molecule several of these mechanisms, thus by fitting into the active site of the enzyme through one part of the molecule and bringing the reactive moiety in close proximity to the catalytic cysteine. This review summarizes novel classes of inhibitors that show specificity for the CDC25s over other phosphatases, cause cell proliferation inhibition and cell cycle arrest in vitro but also, for several of them, inhibition of xenografted tumoral cell growth in vivo. These promising results confirm the interest of the inhibition of CDC25 phosphatases as an anticancer therapeutic strategy.
Tubulin is a validated target for antitumor drugs. However, the effectiveness of these microtubul... more Tubulin is a validated target for antitumor drugs. However, the effectiveness of these microtubule-interacting agents is limited by the fact that they are substrates for drug efflux pumps (P-glycoprotein) and/or by the acquisition of point mutations in tubulin residues important for drug-tubulin binding. To bypass these resistance systems, we have identified and characterized a novel synthetic imidazole derivative IRC-083927, which inhibits the tubulin polymerization by a binding to the colchicine site. IRC-083927 inhibits in vitro cell growth of human cancer cell lines in the low nanomolar range. More interesting, it remains highly active against cell lines resistant to microtubule-interacting agents (taxanes, Vinca alkaloids, or epothilones). Such resistances are due to the presence of efflux pumps (NCI-H69/LX4 resistant to navelbine and paclitaxel) and/or the presence of mutations on beta-tubulin and on alpha-tubulin and beta-tubulin (A549.EpoB40/A549.EpoB480 resistant to epothilone B or paclitaxel). IRC-083927 displayed cell cycle arrest in G(2)-M phase in tumor cells, including in the drug-resistant cells. In addition, IRC-083927 inhibited endothelial cell proliferation in vitro and vessel formation in the low nanomolar range supporting an antiangiogenic behavior. Finally, chronic oral treatment with IRC-083927 (5 mg/kg) inhibits the growth of two human tumor xenografts in nude mice (C33-A, human cervical cancer and MDA-MB-231, human hormone-independent breast cancer). Together, the antitumor effects induced by IRC-083927 on tumor models resistant to tubulin agents support further investigations to fully evaluate its potential for the treatment of advanced cancers, particularly those resistant to current clinically available drugs.
Using a solution-phase parallel synthesis strategy, a series of non-peptide somatostatin analogue... more Using a solution-phase parallel synthesis strategy, a series of non-peptide somatostatin analogues were prepared, and their binding affinities to the five human somatostatin receptor subtypes (sst(1-5)) were determined. Imidazolyl derivatives 2 were found to bind with moderate affinity but with high selectivity to the sst(3) receptor subtype. Further modifications of these structures led to a more potent class of ligands, the tetrahydro-beta-carboline derivatives 4. Among these, compounds 4k (BN81644) and 4n (BN81674) bind selectively and with high affinity to the sst(3) receptor subtype (K(i) = 0.64 and 0.92 nM, respectively). Furthermore, 4k and 4n reverse the inhibition of cyclic AMP accumulation induced by 1 nM somatostatin via sst(3) receptors, with IC(50) = 2.7 and 0.84 nM, respectively. The most potent compound 4n was shown to be a competitive antagonist of human sst(3) receptors by increasing the EC(50) of SRIF-14-mediated inhibition of cAMP accumulation with a K(B) of 2.8 nM (where K(B) is the concentration of antagonist that shifts the agonist dose-response 2-fold). These new derivatives are, to our knowledge, the first potent and highly selective non-peptide human sst(3) antagonists known and, as such, are useful tools for investigating the physiological role of sst(3) receptors.
A series of 2-alkyl-4-arylimidazoles were prepared and their binding affinities to the site-2 sod... more A series of 2-alkyl-4-arylimidazoles were prepared and their binding affinities to the site-2 sodium (Na+) channel were determined. SAR studies led to highly potent Na+ channel blockers.
The CDC25 phosphatases are key regulators of cell cycle progression and play a central role in th... more The CDC25 phosphatases are key regulators of cell cycle progression and play a central role in the checkpoint response to DNA damage. Their inhibition may therefore represent a promising therapeutic approach in oncology, and small molecule design strategies are currently leading to the identification of various classes of CDC25 inhibitors. Most structures developed so far are quinonoid-based compounds, but also phosphate surrogates or electrophilic entities. Considering the characteristics of the highly conserved active sites of the enzymes, many mechanisms of action have been proposed for these inhibitors. Quinonoid compounds may oxidize the catalytic site cysteine, but can also be considered as Michaël acceptors capable of reacting with the activated thiolate or other electrophilic entities. Phosphate surrogates are thought to interfere with the arginine residue, leading to reversible enzyme inhibition. But some inhibitors can combine in the same molecule several of these mechanisms, thus by fitting into the active site of the enzyme through one part of the molecule and bringing the reactive moiety in close proximity to the catalytic cysteine. This review summarizes novel classes of inhibitors that show specificity for the CDC25s over other phosphatases, cause cell proliferation inhibition and cell cycle arrest in vitro but also, for several of them, inhibition of xenografted tumoral cell growth in vivo. These promising results confirm the interest of the inhibition of CDC25 phosphatases as an anticancer therapeutic strategy.
Tubulin is a validated target for antitumor drugs. However, the effectiveness of these microtubul... more Tubulin is a validated target for antitumor drugs. However, the effectiveness of these microtubule-interacting agents is limited by the fact that they are substrates for drug efflux pumps (P-glycoprotein) and/or by the acquisition of point mutations in tubulin residues important for drug-tubulin binding. To bypass these resistance systems, we have identified and characterized a novel synthetic imidazole derivative IRC-083927, which inhibits the tubulin polymerization by a binding to the colchicine site. IRC-083927 inhibits in vitro cell growth of human cancer cell lines in the low nanomolar range. More interesting, it remains highly active against cell lines resistant to microtubule-interacting agents (taxanes, Vinca alkaloids, or epothilones). Such resistances are due to the presence of efflux pumps (NCI-H69/LX4 resistant to navelbine and paclitaxel) and/or the presence of mutations on beta-tubulin and on alpha-tubulin and beta-tubulin (A549.EpoB40/A549.EpoB480 resistant to epothilone B or paclitaxel). IRC-083927 displayed cell cycle arrest in G(2)-M phase in tumor cells, including in the drug-resistant cells. In addition, IRC-083927 inhibited endothelial cell proliferation in vitro and vessel formation in the low nanomolar range supporting an antiangiogenic behavior. Finally, chronic oral treatment with IRC-083927 (5 mg/kg) inhibits the growth of two human tumor xenografts in nude mice (C33-A, human cervical cancer and MDA-MB-231, human hormone-independent breast cancer). Together, the antitumor effects induced by IRC-083927 on tumor models resistant to tubulin agents support further investigations to fully evaluate its potential for the treatment of advanced cancers, particularly those resistant to current clinically available drugs.
Using a solution-phase parallel synthesis strategy, a series of non-peptide somatostatin analogue... more Using a solution-phase parallel synthesis strategy, a series of non-peptide somatostatin analogues were prepared, and their binding affinities to the five human somatostatin receptor subtypes (sst(1-5)) were determined. Imidazolyl derivatives 2 were found to bind with moderate affinity but with high selectivity to the sst(3) receptor subtype. Further modifications of these structures led to a more potent class of ligands, the tetrahydro-beta-carboline derivatives 4. Among these, compounds 4k (BN81644) and 4n (BN81674) bind selectively and with high affinity to the sst(3) receptor subtype (K(i) = 0.64 and 0.92 nM, respectively). Furthermore, 4k and 4n reverse the inhibition of cyclic AMP accumulation induced by 1 nM somatostatin via sst(3) receptors, with IC(50) = 2.7 and 0.84 nM, respectively. The most potent compound 4n was shown to be a competitive antagonist of human sst(3) receptors by increasing the EC(50) of SRIF-14-mediated inhibition of cAMP accumulation with a K(B) of 2.8 nM (where K(B) is the concentration of antagonist that shifts the agonist dose-response 2-fold). These new derivatives are, to our knowledge, the first potent and highly selective non-peptide human sst(3) antagonists known and, as such, are useful tools for investigating the physiological role of sst(3) receptors.
A series of 2-alkyl-4-arylimidazoles were prepared and their binding affinities to the site-2 sod... more A series of 2-alkyl-4-arylimidazoles were prepared and their binding affinities to the site-2 sodium (Na+) channel were determined. SAR studies led to highly potent Na+ channel blockers.
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Papers by Dennis Bigg