Most malaria drug development focuses on parasite stages detected in red-blood cells even though to achieve eradication next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4,000 commercially available compounds with previously demonstrated blood stage activity (IC50 < 1 μM), and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. Our orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 mg/kg) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.
The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.
Visceral
leishmaniasis is responsible for up to 30,000 deaths every
year. Current treatments have shortcomings that include toxicity and
variable efficacy across endemic regions. Previously, we reported
the discovery of GNF6702, a selective inhibitor of the kinetoplastid
proteasome, which cleared parasites in murine models of leishmaniasis,
Chagas disease, and human African trypanosomiasis. Here, we describe
the discovery and characterization of LXE408, a structurally related
kinetoplastid-selective proteasome inhibitor currently in Phase 1
human clinical trials. Furthermore, we present high-resolution cryo-EM
structures of the
Leishmania tarentolae
proteasome
in complex with LXE408, which provides a compelling explanation for
the noncompetitive mode of binding of this novel class of inhibitors
of the kinetoplastid proteasome.
A series of 2-amino-9-aryl-7H-pyrrolo[2,3-d]pyrimidines were designed and synthesized as focal adhesion kinase (FAK) inhibitors using molecular modeling in conjunction with a co-crystal structure. Chemistry was developed to introduce functionality onto the 9-aryl ring, which resulted in the identification of potent FAK inhibitors. In particular, compound 32 possessed single-digit nanomolar IC(50) and represents one of the most potent FAK inhibitors discovered to date.
Farnesoid X receptor
(FXR) agonists are emerging as important potential
therapeutics for the treatment of nonalcoholic steatohepatitis (NASH)
patients, as they exert positive effects on multiple aspects of the
disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular
inflammation, hepatic injury, and fibrosis. While there are currently
no approved therapies for NASH, the bile acid-derived FXR agonist
obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise
in clinical studies. Previously, we described the discovery of tropifexor
(LJN452), the most potent non-bile acid FXR agonist currently in clinical
investigation. Here, we report the discovery of a novel chemical series
of non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole
core from which emerged nidufexor (LMB763), a compound with partial
FXR agonistic activity in vitro and FXR-dependent
gene modulation in vivo. Nidufexor has advanced to
Phase 2 human clinical trials in patients with NASH and diabetic nephropathy.
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