Professor, Faculty of Pharmacy, University OF MONTPELLIER
Vincent Lisowski was born in Aunay/Odon (France) in 1974. He first received his PharmD degree in 1998 before he obtained his PhD in 2002 from the University of Basse-Normandie, under the supervision of Professor Sylvain Rault in the field of new thiophene-based chemotherapeutic agents. After a postdoctoral position at the pharmaceutical faculty of Caen, where he developed medicinal projects in the field of cancer and Alzheimer’s disease, he joined the group of Professor Jean Martinez as an Assistant Professor at the University of Montpellier, in 2003. He was appointed Professor of Medicinal Chemistry at the School of Pharmacy in 2012. His research interests are peptide & heterocyclic chemistry applied to projects in the fields of medicinal chemistry (enzyme inhibitors, drug delivery) and chemical biology (antibody drug conjugate)
5 major publications :
Masurier, Arama, D.P.; N; El Amri, C.; Lisowski, V. Physiological and synthetic inhibitors of tissue kallikreins: an overview. Med. Res. Rev., 2017, accepted.
Mathieu, L.; Bonnel, C.; Masurier, N.; Maillard, L. T.; Martinez, J.; Lisowski, V. Cross-Claisen Condensation of N-Fmoc-Amino Acids – A Short Route to Heterocyclic gamma-Amino Acids. European Journal of Organic Chemistry 2015, 2262-2270.
Denoyelle, S.; Tambutet, G.; Masurier, N.; Maillard, L. T.; Martinez, J.; Lisowski, V. Synthesis of Thieno[3,2-e][1,4]diazepin-2-ones: Application of an Uncatalysed Pictet-Spengler Reaction. European Journal of Organic Chemistry 2015, 7146-7153.
Legrand, B.; Mathieu, L.; Lebrun, A.; Andriamanarivo, S.; Lisowski, V.; Masurier, N.; Zirah, S.; Kang, Y. K.; Martinez, J.; Maillard, L. T. Thiazole-Based gamma-Building Blocks as Reverse-Turn Mimetic to Design a Gramicidin S Analogue: Conformational and Biological Evaluation. Chemistry-a European Journal 2014, 20, 6713-6720.
Malcor, J.-D.; Payrot, N.; David, M.; Faucon, A.; Abouzid, K.; Jacquot, G.; Floquet, N.; Debarbieux, F.; Rougon, G.; Martinez, J.; Khrestchatisky, M.; Vlieghe, P.; Lisowski, V. Chemical Optimization of New Ligands of the Low-Density Lipoprotein Receptor as Potential Vectors for Central Nervous System Targeting. Journal of Medicinal Chemistry 2012, 55, 2227-2241.
Identification of Quinazolinone Analogs Targeting CDK5 Kinase Activity and Glioblastoma Cell Proliferation
Front Chem. 2020; 8: 691. https://doi.org/10.3389/fchem.2020.00691
Marion Peyressatre, Dominique Patomo Arama, Arthur Laure, Juan A. González-Vera, Morgan Pellerano, Nicolas Masurier, Vincent Lisowski, May C. Morris
CDK5/p25 kinase plays a major role in neuronal functions, and is hyperactivated in several human cancers including glioblastoma and neurodegenerative pathologies such as Alzheimer’s and Parkinson’s. CDK5 therefore constitutes an attractive pharmacological target. Since the successful discovery and development of Roscovitine, several ATP-competitive inhibitors of CDK5 and peptide inhibitors of CDK5/p25 interface have been developed. However, these compounds suffer limitations associated with their mechanism of action and nature, thereby calling for alternative targeting strategies. To date, few allosteric inhibitors have been developed for successful targeting of protein kinases. Indeed, although this latter class of inhibitors are believed to be more selective than compounds targeting the active site, they have proven extremely difficult to identify in high throughput screens. By implementing a fluorescent biosensor that discriminates against ATP-pocket binding compounds to screen for allosteric inhibitors that target conformational activation of CDK5, we have identified a novel family of quinazolinones. Characterization of these hits and several of their derivatives revealed their inhibitory potential toward CDK5 kinase activity in vitro and to inhibit glioblastoma cell proliferation. The quinazolinone derivatives described in this study are the first small molecules reported to target CDK5 at a site other than the ATP pocket, thereby constituting attractive leads for glioblastoma therapeutics and providing therapeutic perspectives for neurodegenerative diseases. These compounds offer alternatives to conventional ATP-competitive inhibitors or peptides targeting CDK5/p25 interface with the potential of bypassing their limitations.
The HslV Protease from Leishmania major and Its Activation by C-terminal HslU Peptides
Int J Mol Sci. 2019 Feb 26;20(5). pii: E1021. doi: 10.3390/ijms20051021
Kebe NM, Samanta K, Singh P, Lai-Kee-Him J, Apicella V, Payrot N, Lauraire N, Legrand B, Lisowski V, Mbang-Benet DE, Pages M, Bastien P, Kajava AV, Bron P, Hernandez JF, Coux O
HslVU is an ATP-dependent proteolytic complex present in certain bacteria and in the mitochondrion of some primordial eukaryotes, including deadly parasites such as Leishmania. It is formed by the dodecameric protease HslV and the hexameric ATPase HslU, which binds via the C-terminal end of its subunits to HslV and activates it by a yet unclear allosteric mechanism. We undertook the characterization of HslV from Leishmania major (LmHslV), a trypanosomatid that expresses two isoforms for HslU, LmHslU1 and LmHslU2. Using a novel and sensitive peptide substrate, we found that LmHslV can be activated by peptides derived from the C-termini of both LmHslU1 and LmHslU2. Truncations, Ala- and D-scans of the C-terminal dodecapeptide of LmHslU2 (LmC12-U2) showed that five out of the six C-terminal residues of LmHslU2 are essential for binding to and activating HslV. Peptide cyclisation with a lactam bridge allowed shortening of the peptide without loss of potency. Finally, we found that dodecapeptides derived from HslU of other parasites and bacteria are able to activate LmHslV with similar or even higher efficiency. Importantly, using electron microscopy approaches, we observed that the activation of LmHslV was accompanied by a large conformational remodeling, which represents a yet unidentified layer of control of HslV activation.
Inhibitors of kallikrein-related peptidases: An overview.
Med Res Rev. 2018 Mar;38(2):655-683. doi: 10.1002/med.21451.
Masurier N, Arama DP, El Amri C, Lisowski V.
Kallikrein-related peptidases (KLKs) are a family of 15 secreted serine proteases that are involved in various physiological processes. Their activities are subtly regulated by various endogenous inhibitors, ranging from metallic ions to macromolecular entities such as proteins. Furthermore, dysregulation of KLK activity has been linked to several pathologies, including cancer and skin and inflammatory diseases, explaining the numerous efforts to develop KLK-specific pharmacological inhibitors as potential therapeutic agents. In this review, we focus on the huge repertoire of KLKs inhibitors reported to date with a special emphasis on the diversity of their molecular mechanisms of inhibition.
Structure-Activity Relationships of JMV4463, a Vectorized Cathepsin D Inhibitor with Antiproliferative Properties: The Unique Role of the AMPA-Based Vector
ChemMedChem, 2016, Volume: 11, Issue: 3, Pages: 302-308, DOI: 10.1002/cmdc.201500457
L. Vezenkov, C. A. Sanchez, V. Bellet, V. Martin, M. Maynadier, N. Bettache, V. Lisowski, J. Martinez, M. Garcia, M. Amblard, J. F. Hernandez
Cathepsin D (CathD) is overexpressed and secreted by several solid tumors and stimulates their growth, the mechanism of which is still not understood. In this context, the pepstatin bioconjugate JMV4463 [Ac-arg-O2Oc-(Val)3-Sta-Ala-Sta-(AMPA)4-NH2; O2Oc=8-amino-3,6-dioxaoctanoyl, Sta=statine, AMPA=ortho-aminomethylphenylacetyl], contg. a new kind of cell-penetrating vector, was previously shown to exhibit potent antiproliferative effects in vitro and to delay the onset of tumors in vivo. In this study, the authors performed a structure-activity relationship anal. to evaluate the significance of the inhibitor and vector moieties of JMV4463. By modifying both statine residues of pepstatin the authors found that the antiproliferative activity is correlated with CathD inhibition, supporting a major role of the catalytic activity of intracellular CathD in cancer cell proliferation. Replacing the vector composed of four AMPA units with other vectors was found to abolish cytotoxicity, although all of the conjugates enabled pepstatin transport into cells. In addn., the AMPA4 vector must be localized at the C terminus of the bioconjugate. The unexpected importance of the vector structure and position for cytotoxic action suggests that AMPA4 enables pepstatin to inhibit the proteolysis of crit. CathD substrates involved in cell proliferation via a unique mechanism of action.
Pyrido-imidazodiazepinones as a new class of reversible inhibitors of human kallikrein 7
European Journal of Medicinal Chemistry, 2015, Volume: 93, Pages: 202-213, DOI: 10.1016/j.ejmech.2015.02.008
D. P. Arama, F. Soualmia, V. Lisowski, J.-F. Longevial, E. Bosc, L. T. Maillard, J. Martinez, N. Masurier, C. El Amri
The human tissue kallikrein-7 (KLK7) is a chymotryptic serine protease member of tissue kallikrein family. KLK7 is involved in skin homeostasis and inflammation. Excess of KLK7 activity is also assocd. with tumor metastasis processes, esp. in ovarian carcinomas, prostatic and pancreatic cancers. Development of Kallikrein 7 inhibitors is thus of great interest in oncol. but also for treating skin diseases. Most of the developed synthetic inhibitors present several drawbacks such as poor selectivity and unsuitable physico-chem. properties for in vivo use. Recently, the authors described a practical sequence for the synthesis of imidazopyridine-fused [1,3]-diazepines. Here, the authors report the identification of pyrido-imidazodiazepinone core as a new potential scaffold to develop selective and competitive inhibitors of kallikrein-related peptidase 7. Structure-activity relationships (SAR), inhibition mechanisms and selectivity as well as cytotoxicity against selected cancer cell lines were investigated.
Cross-Claisen condensation of N-Fmoc-amino acids – a short route to heterocyclic γ-amino acids
European Journal of Organic Chemistry, 2015, Volume: 2015, Issue: 10, Pages: 2262-2270, DOI: 10.1002/ejoc.201500012
L. Mathieu, C. Bonnel, N. Masurier, L. T. Maillard, J. Martinez, V. Lisowski
4-Amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) are a new class of constrained heterocyclic γ-amino acids built around a thiazole ring; these compds. are valuable as design mimics of the secondary structures of proteins such as helixes, β-sheets, turns, and β-hairpins. We report herein a short and versatile chem. route to orthogonally protected ATCs. The synthesis is centered on cross-Claisen condensations between N-Fmoc-amino acids and sterically hindered 1,1-dimethylallyl acetate. The optimized conditions are compatible with aliph., arom., acidic, and basic amino acids. The resulting N-Fmoc-β-keto ester intermediates were engaged in a two-step process to give ATCs in 45-90 % yields. The synthetic protocol provides a highly flexible method for the introduction of a wide variety of lateral chains either on the γ-carbon atom or on the thiazole core of the γ-amino acids.
Synthesis of Thieno[3,2-e][1,4]diazepin-2-ones: Application of an Uncatalysed Pictet-Spengler Reaction
European Journal of Organic Chemistry, 2015, Volume: 2015, Issue: 32, Pages: 7146-7153, DOI: 10.1002/ejoc.201500943
S. Denoyelle, G. Tambutet, N. Masurier, L. T. Maillard, J. Martinez, V. Lisowski
A series of 5-substituted thieno[3,2-e][1,4]diazepin-2-ones was synthesized in four steps from Me 3-aminothiophene-2-carboxylate. After the coupling of 3-aminothiophene with α-amino acids, the key final step that involves an uncatalyzed Pictet-Spengler reaction allowed the cyclization of the seven-membered diazepinone ring. The reaction was first optimized and then exemplified in three different series (phenylalanine, alanine and proline) that led to 24 target diazepinones, which includes 19 optically pure diastereomers.
Imidazopyridine-fused [1,3]-diazepinones: Synthesis and antiproliferative activity
European Journal of Medicinal Chemistry, 2014, Volume: 75, Pages: 382-390, DOI: 10.1016/j.ejmech.2014.01.044
A. Gallud, O. Vaillant, L.T. Maillard, D. Arama, J. Dubois, M. Maynadier, V. Lisowski, M. Garcia, J. Martinez, N. Masurier
A series of 15 pyrido-imidazo-1,3-diazepin-5-ones and pyrido-1,3-diazepine-2,5-diones were synthesized and their anticancer activities were evaluated. Among tested compds. on a cell lines panel, compd. I presents the best growth inhibition activity on 21 cell lines with a cytotoxic effect on MDA-MB-435 melanoma cells. This compd. led to deep cell morphol. changes and revealed to be an inhibitor of the Hepatocyte progenitor kinase-like kinase (HGK), which is known to be implicated in the migration, adhesion and invasion of various tumor cells.
Synthesis and reactivity of pyrrolo[3,2-d][1,3]oxazine-2,4-dione. Access to new pyrrolo[3,2-e][1,4]diazepine-2,5-diones
Tetrahedron, 2014, Volume: 70, Issue: 31, Pages: 4631-4639, DOI: 10.1016/j.tet.2014.05.046
J. Malcor, Y. Brouillette, J. Graffion, K. Spielmann, N. Masurier, L. T. Maillard, J. Martinez, V. Lisowski
A convenient synthesis of pyrrolo[3,2-d][1,3]oxazine-2,4-dione is described and its reactivity towards various nucleophiles studied. The regioselective ring opening of pyrrolo[3,2-d][1,3]oxazine-2,4-dione or its N-alkylated analog in the presence of alanine or proline afforded, resp., imidazolidinedione and 2 N-protected pyrrolo[3,2-e][1,4]diazepines in a one-pot process. In a last part of this study, an alternative route to produce a library of eight non protected pyrrolo[3,2-e][1,4]diazepine-2,5-diones is described to overcome the limited reactivity of pyrrolo[3,2-d][1,3]oxazine-2,4-dione.
Thiazole-based γ-building blocks as reverse-turn mimetic to design a Gramicidin S analogue: Conformational and biological evaluation
Chemistry – A European Journal, 2013, Volume: 20, Issue: 22, Pages: 6713-6720, DOI: 10.1002/chem.201402190
B. Legrand, L. Mathieu, A. Lebrun, S. Andriamanarivo, V. Lisowski, N. Masurier, S. Zirah, Y. Kang, J. Martinez, L. Maillard
This paper describes the ability of a new class of heterocyclic γ-amino acids named ATCs (4-amino(methyl)-1,3-thiazole-5-carboxylic acids) to induce turns when included in a tetrapeptide template. Both hybrid Ac-Val-(R or S)-ATC-Ile-Ala-NH2 sequences were synthesized and their conformations were studied by CD, NMR spectroscopy, MD simulations, and DFT calcns. It was demonstrated that the ATCs induced highly stable C9 pseudocycles in both compds. promoting a twist turn and a reverse turn conformation depending on their abs. configurations. As a proof of concept, a bioactive analog of gramicidin S was successfully designed using an ATC building block as a turn inducer. The NMR soln. structure of the analog adopted an antiparallel β-pleated sheet conformation similar to that of the natural compd. The hybrid α,γ-cyclopeptide exhibited significant reduced hemotoxicity compared to gramicidin S, while maintaining strong antibacterial activity.