In medicinal chemistry, one of the big challenges remains the discovery of an original hit that can be easily tuned into a lead and then in a drug candidate. In this regard, our aim is to develop an innovative fragment-to-lead strategy for high-quality lead identification. This computationally-assisted approach involves the initial discovery of low-molecular weight molecules called fragments. Owing to their small-size, fragments are more likely to reach key pockets within a protein active site, and, once their interaction within the active site is clearly understood, they represent a unique possibility of designing a promising hit compound in an efficient way.
The originality of this approach resides in the compilation of available experimental information about structural motifs recognized by the target, and their use to guide the selection of fragments from large chemical databases using a computationally-assisted screening. The interaction of chosen fragments with the target protein can then be experimentally assessed by means of biochemical and biophysical techniques, such as NMR, surface plasmon resonance (SPR), mass spectrometry (MS) and/or X-ray diffraction (XRD). Once the binding experimentally confirmed, rational drug design can start and the selected fragments can be finely tuned to provide an original hit. This original computationally-assisted fragment-to-lead strategy offers the prospect of a more efficient approach to drug discovery – resulting in the generation of high-quality leads with a better chance of success in future development.
Tryptophan catabolism is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance, and indoleamine 2,3-dioxygenases (IDO and TDO) inhibition is a promising strategy for anticancer drug development. IDO and TDO are unrelated heme-containing enzymes catalyzing the oxidative cleavage of the indole ring of L-tryptophan (L-Trp), the first and rate-limiting step along the kynurenine pathway. The implication of IDO in the phenomenon of tumoral immune resistance is the focus of intense researches and the enzyme is now recognized as a validated target for anti-cancer therapy. Therefore, a number of groups, including us, are actively searching for novel original IDO inhibitors. In contrast, the effect of TDO expression on the immune response has only been recently investigated in detail. Indeed, we showed in collaboration with the group of Prof Van den Eynde that TDO was effectively overexpressed by a number of human tumors and that this expression prevented rejection of tumor cells. We designed a novel TDO inhibitor and proved, in a preclinical model, the concept that TDO inhibition promotes tumoral immune rejection. Interestingly, blocking both TDO and IDO to improve the efficacy of cancer immunotherapy would be complementary: in a series of 104 human tumor lines of various histological types, we showed that 20 tumors expressed only TDO, 17 only IDO and 16 expressed both enzymes. Therefore, targeting both IDO and TDO would allow reaching 51% of tumors instead of either 32% or 35% with a compound inhibiting IDO or TDO alone, respectively. The design of IDO, TDO or dual IDO/TDO inhibitors is thus of major importance. Interestingly, our fragment-based drug design strategy recently provided promising results for the discovery of new IDO. These preliminary data are very encouraging to pursue the search for new anticancer agents through a fragment-based drug design strategy.
This project aims to understand the role of the serine pathway in tumor progression and in particular to develop pharmacological tools to evaluate the extent of tumor addiction to this metabolic path and their therapeutic potential by exploring potential side effects on healthy tissues. To this end, novel innovative pharmacological inhibitors of PHGDH and PSAT1, the two main enzymes of the serine pathway (see Figure 1), will be designed and chemically synthesized. These compounds will help deciphering the exact roles of these enzymes in cancer progression and will provide insights on their physiological roles (that could represent limitations to the clinical use of such inhibitors).
The last five years have witnessed an increased regain of interest for tumor metabolism. Recent advances in this field have shed light on how tumors fuel rapid growth by preferentially engaging biosynthetic pathways. Although cellular metabolic pathways are rich pickings for drug targets, pinpointing enzymes that critically contribute to tumor metabolism is key to establish a therapeutic window since most of metabolic enzymes also play important roles in normal tissues. PHGDH (3-phosphoglycerate dehydrogenase) and PSAT1 (phosphoserine aminotransferase-1) could however represent such ideal targets for new anticancer strategies. These enzymes catalyze the first and second steps in the serine biosynthetic pathway, respectively. This pathway diverts a relatively small fraction of 3-phosphoglycerate from glycolysis to generate serine as well as equimolar amounts of NADH and α-ketoglutarate (αKG). Interestingly, two simultaneous recent reports have recently identified the serine pathway as a vital source of αKG to fuel the TCA cycle in a variety of tumor cells. These two studies further documented that serine supplement could not rescue tumor cells in which PHGDH and PSAT1 genes were knocked down, thereby identifying the serine pathway as a process providing malignant cells with critical amounts of its intermediary synthetic products, αKG and possibly NADH, instead of the end product, serine (that may also be taken up from the extracellular fluid). In good agreement with the above statement on the rationale to identify specific targets to tackle tumor metabolism, this latter observation indicates that serine deficiency in healthy tissues and possible disorders associated with the
inhibition of either PHGDH or PSAT1 could be treated by exogenous serine supplement, whereas treatment with such inhibitory compounds could take advantage of the strict addiction of tumors to the by-products resulting from PHGDH and PSAT1 activation.
As the phenomenon of antibiotic resistance is dramatically increasing these days, the search for new therapeutic targets less vulnerable to these resistance mechanisms appears as a real need. The cell wall of bacteria and the enzymes that are involved in its synthesis are prime targets for many antibiotics, which inhibit the late stages of peptidoglycan biosynthetic pathway. But the resistance phenomena have revealed the high flexibility in this assembly pathway, and the need to target other enzymes acting on earlier steps of peptidoglycan synthesis. Dalanyl-D-alanine ligase (Ddl) is of particular interest as it utilizes a substrate (D-alanine) which is specific for bacterial peptidoglycan biosynthesis and essential for bacterial growth.
In this work, we aim at designing novel DDligases inhibitors. Previous works in our group have highlighted a novel hit (S89) characterized with hiosemicarbazide motif. First, analogues of S89 were synthesized. Indeed, the thiosemicarbazide family is very promising due to its low half maximal effective concentration (EC50) and its good antibacterial activity. These compounds will be evaluated on recombinant protein Ddl-His6 produced and purified in our group.
This study will provide initial structureactivity relationships (SAR) and thus help understanding the structure requirements to achieve a high DD-ligases inhibition. Then, novel hits will be identified through a fragment-based strategy. To this end, an inhouse library of 280 diverse fragments will be first assessed. Finally, the more potent fragments will undergo a structure guided optimization to design potent DD-ligases inhibitors.
The aim of this work is to design new bioactive molecules interacting with a physiological system of neurotransmission:
the endocannabinoid system. This system consists in several proteins regulating the signaling of endogenous lipid compounds, i.e. the endocannabinoids. Several targets emerge from this system: endocannabinoid biosynthesis enzymes, GPCR receptors, nuclear receptors and endocannabinoid degradation enzymes.
Ongoing research involves the development of selective inhibitors for the three main enzymes involved in the degradation of the endocannabinoids, namely the fatty acid amide hydrolase (type I), the monoacylglycerollipase, the N-acylethanolamine Acid Amidase. Several inhibitors of endocannabinoids metabolism have been discovered. The main achievement was the synthesis of the first inhibitor of the N-acylethanolamine Acid Amidase. Regarding monoacylglycerollipase (MGL), the search was focused on selective inhibitors, disulfiram has been identified as MGL inhibitor with a high selectivity profile regarding fatty acid amide hydrolase (type I).
Infections caused by trypanosomes remain a severe health problem in Western Africa. Some treatments are available. However, the useful drugs are rather expensive and induce severe side-effects. There is therefore an urgent need to provide the medical community with new improved drugs. Along this line, we launched a medicinal chemistry research program using acetophenone thiosemicarbazone as lead compound. Initial work was devoted to getting access to a flexible and "green" access route to these target compounds by development of an efficient catalysis. After having synthesized a compound library of some 150 terms, we ended up with compounds with IC50's in the sub-micromolar range endowed with a rather good safety index (~100). Further work is now being performed to expand the druggability within this series.
Besides our main research topics, we are offering our technological chemical and pharmacological expertise in to other research scientists from UCL or external groups.