Update on glasdegib in acute myeloid leukemia – broadening horizons of Hedgehog pathway inhibitors

Numerous new emerging therapies, including oral targeted chemotherapies, have recently entered the therapeutic arsenal against acute myeloid leukemia (AML). The significant shift toward the use of these novel therapeutics, administered either alone or in combination with intensive or low-intensity chemotherapy, changes the prospects for the control of this disease, especially for elderly patients. Glasdegib, an oral Hedgehog pathway inhibitor, showed satisfactory response rates associated with moderate toxicity and less early mortality than standard induction regimens in this population. It was approved in November 2018 by the FDA and in June 2020 by the EMA for use in combination with low-dose cytarabine as a treatment of newly-diagnosed AML in patients aged ≥ 75 and/or unfit for intensive induction chemotherapy. The current paper proposes an extensive, up-to-date review of the preclinical and clinical development of glasdegib. Elements of its routine clinical use and the landscape of ongoing clinical trials are also stated

Antikinetoplastid SAR study in 3-nitroimidazopyridine series:identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties.

International audienceTo study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = −0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program

8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases

Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 mu M range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 mu M) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 mu M), slightly lower than the one of miltefosine (IC50 = 4.3 mu M). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 mu M) and selective (SI = >313 to 550) molecules toward T brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 mu M). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTRI), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V

Nongenotoxic 3-Nitroimidazo[1,2-a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity

Twenty nine original 3-nitroimidazo[1,2-a]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC50 > 100 mu M) alongside good antileishmanial activities (IC50 = 1-2.1 mu M) against L. donovani, L. infantum, and L. major; and good antitrypanosomal activities (IC50 = 1.3-2.2 mu M) against T. brucei brucei and T. cruzi, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine, and benznidazole (IC50 = 0.6 to 13.3 mu M). Molecule 5, presenting a low reduction potential (E degrees = -0.63 V), was shown to be selectively bioactivated by the L. donovani type 1 nitroreductase (NTR1). Importantly, molecule 5 was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule 5 showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and nonmutagenic, making 5 a good candidate for further in vivo studies

Antikinetoplastid SAR study in 3-nitroimidazopyridine series: identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties

To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program

Synthesis and structure-activity relationships study of new anti-kinetoplastid 3-nitroimidazo[1,2-a]pyridines

Les maladies tropicales négligées causées par les protozoaires kinétoplastidés du genre Leishmania et Trypanosoma représentent une menace pour près d’un demi-milliard de personnes en zone intertropicale, entrainant jusqu’à 50 000 décès par an. Parmi les molécules en développement clinique pour traiter ces pathologies, le fexinidazole est une prodrogue appartenant à la famille des 5-nitroimidazoles et qui exerce son action anti-infectieuse via une étape de bioactivation catalysée par des nitroréductases (NTR) parasitaires, enzymes dont le co-facteur est une flavine. Afin d’identifier de nouveaux nitrohétérocycles antiparasitaires substrats des NTR, une petite chimiothèque d’imidazo[1,2-a]pyridines synthétisées au laboratoire a subi un criblage in vitro ayant conduit à l’identification d’une molécule Hit, à la fois active sur Leishmania donovani et Trypanosoma brucei brucei. Ce composé a servi de point de départ à un travail de pharmacomodulation, dans un premier temps en position 8 du cycle imidazo[1,2-a]pyridine : l’introduction de groupements variés à l’aide de réactions de couplage pallado-catalysées de Suzuki-Miyaura, Sonogashira et Buchwald-Hartwig ou des réactions de SNAr, a permis de mettre en lumière plusieurs composés « tête de série » au profil biologique nettement amélioré. Dans un second temps, le travail de pharmacomodulation entrepris a été étendu aux positions 2, 3 et 6 du cycle imidazo[1,2-a]pyridine en vue de compléter les données de relations structure-activité, d’étudier en particulier l’impact du potentiel rédox et d’optimiser les paramètres physico-chimiques et pharmacocinétiques in vitro des meilleurs composés.The kinetoplastids of the Leishmania and Trypanosoma genus are the causative agents of neglected tropical diseases that threaten nearly half a billion people in the intertropical zone, resulting in 50 000 deaths per year. Among the molecules in clinical development to treat these pathologies, fexinidazole is a prodrug belonging to the 5-nitroimidazoles family, which exerts its anti-infectious action via a bioactivation step catalyzed by parasitic nitroreductases (NTR), enzymes whose cofactor is a flavin. In order to identify novel nitroheterocycles as parasitic NTR substrates, a small chemical library of imidazo[1,2-a]pyridines synthesized by our laboratory was screened in vitro, leading to the identification of a Hit molecule active both on Leishmania donovani and Trypanosoma brucei brucei. This compound served as a starting point for a pharmacomodulation work, initially in position 8 of the imidazo[1,2-a]pyridine ring: the introduction of various chemical groups using the pallado-catalyzed coupling reactions of Suzuki-Miyaura, Sonogashira and Buchwald-Hartwig, or SNAr reactions, highlighted several "lead" compounds with a significantly improved biological profile. In a second step, the pharmacomodulation work was extended to positions 2, 3 and 6 of the imidazo[1,2-a]pyridine ring in order to complete the structure-activity relationship data, to study in particular the impact of the redox potential and to optimize the physicochemical and in vitro pharmacokinetic parameters of the best compounds in order to initiate the study of their in vivo activity on a trypanosomiasis mouse model

Thienopyrimidine: A Promising Scaffold to Access Anti-Infective Agents

Thienopyrimidines are widely represented in the literature, mainly due to their structural relationship with purine base such as adenine and guanine. This current review presents three isomers—thieno[2,3-d]pyrimidines, thieno[3,2-d]pyrimidines and thieno[3,4-d]pyrimidines—and their anti-infective properties. Broad-spectrum thienopyrimidines with biological properties such as antibacterial, antifungal, antiparasitic and antiviral inspired us to analyze and compile their structure–activity relationship (SAR) and classify their synthetic pathways. This review explains the main access route to synthesize thienopyrimidines from thiophene derivatives or from pyrimidine analogs. In addition, SAR study and promising anti-infective activity of these scaffolds are summarized in figures and explanatory diagrams. Ligand–receptor interactions were modeled when the biological target was identified and the crystal structure was solved

AAZTA-Derived Chelators for the Design of Innovative Radiopharmaceuticals with Theranostic Applications

International audienceWith the development of 68Ga and 177Lu radiochemistry, theranostic approaches in modern nuclear medicine enabling patient-centered personalized medicine applications have been growing in the last decade. In conjunction with the search for new relevant molecular targets, the design of innovative chelating agents to easily form stable complexes with various radiometals for theranostic applications has gained evident momentum. Initially conceived for magnetic resonance imaging applications, the chelating agent AAZTA features a mesocyclic seven-membered diazepane ring, conferring some of the properties of both acyclic and macrocyclic chelating agents. Described in the early 2000s, AAZTA and its derivatives exhibited interesting properties once complexed with metals and radiometals, combining a fast kinetic of formation with a slow kinetic of dissociation. Importantly, the extremely short coordination reaction times allowed by AAZTA derivatives were particularly suitable for short half-life radioelements (i.e., 68Ga). In view of these particular characteristics, the scope of this review is to provide a survey on the design, synthesis, and applications in the nuclear medicine/radiopharmacy field of AAZTA-derived chelators

Tailored Media-Fill Test Protocols Inspired by 68 Ga Kit-Based Radiopharmaceuticals

Gallium-68 radiolabeling is an increasingly common activity in radiopharmacy. Single vial cold kits to radiolabel DOTATOC and PSMA-11 with 68Ga were developed, either for manual or automated preparation. Both approaches are very specific and require aseptic compounding skills, raising the need for dedicated training. The aim of this work was to design and implement an integrative media-fill test (MFT) protocol inspired by 68Ga kit-based radiopharmaceuticals for operator qualification, suitable for both manual and automated preparation simulations. Three custom MFT protocols (two manual and one automated simulations) compatible with specific radiopharmacy equipment were designed for operator training. During MFT sessions, the microbiological quality of the working environment was monitored by surface and air sampling. The sensitivity of the tryptic soy broth (TSB) and the influence of the number of punctures performed in each vial on the units positivity were also studied. Four operators were evaluated and carried out in triplicate the three MFTs. None of the 336 incubated units showed turbidity, although 27.8% of surface samples and 11.1% of air samples were positive (1-4 CFU). Over 36 MFT sessions, 15 contaminations of the working area by TSB drops occurred. TSB sensitivity was estimated >3.12 UFC. Units positivity showed a probable relationship with the number of punctures in a vial and, more obviously, with the contamination level of the vial stopper. As a part of a general sterile compounding instruction, these MFT protocols may be useful tools for initial and continuing training of operators carrying out manual and automated 68Ga radiolabeling

A Comprehensive Review of Non-Covalent Radiofluorination Approaches Using Aluminum [18F]fluoride: Will [18F]AlF Replace 68Ga for Metal Chelate Labeling?

Due to its ideal physical properties, fluorine-18 turns out to be a key radionuclide for positron emission tomography (PET) imaging, for both preclinical and clinical applications. However, usual biomolecules radiofluorination procedures require the formation of covalent bonds with fluorinated prosthetic groups. This drawback makes radiofluorination impractical for routine radiolabeling, gallium-68 appearing to be much more convenient for the labeling of chelator-bearing PET probes. In response to this limitation, a recent expansion of the 18F chemical toolbox gave aluminum [18F]fluoride chemistry a real prominence since the late 2000s. This approach is based on the formation of an [18F][AlF]2+ cation, complexed with a 9-membered cyclic chelator such as NOTA, NODA or their analogs. Allowing a one-step radiofluorination in an aqueous medium, this technique combines fluorine-18 and non-covalent radiolabeling with the advantage of being very easy to implement. Since its first reports, [18F]AlF radiolabeling approach has been applied to a wide variety of potential PET imaging vectors, whether of peptidic, proteic, or small molecule structure. Most of these [18F]AlF-labeled tracers showed promising preclinical results and have reached the clinical evaluation stage for some of them. The aim of this report is to provide a comprehensive overview of [18F]AlF labeling applications through a description of the various [18F]AlF-labeled conjugates, from their radiosynthesis to their evaluation as PET imaging agents