To date, there are no current orally available compounds that promote bone formation for treating osteoporosis; most treatments act by inhibiting osteoclastic bone resorption, leading to increased bone mineral density and reduced hip fracture rate in a modest way. Analogues of parathyroid hormone (PTH) are the most frequently used bone anabolic agents, which even though effective, they require daily injections.
Type I JAK2 inhibitors improve symptoms and outcomes of patients with myeloproliferative neoplasms (MPNs), but mutant allele JAK2 VF remains unchanged with this therapy. Type II JAK2 inhibitors bind the inactive conformation of the kinase domain and reduce the fraction of JAK2 VF mutant allele in vivo, suggesting an improved approach for JAK2 inhibition. Ajax Pharmaceuticals Inc. presented preclinical data on the type II JAK2 inhibitor AJ1-10502 for the treatment of MPNs.
Hepcidin deficiency in hereditary hemochromatosis (HH) leads to increased absorption of dietary iron and thus iron overload. Rusfertide is a hepcidin mimetic peptide that has shown efficacy at reducing the need for therapeutic maintenance phlebotomy in patients with HH. Researchers aimed to evaluate the benefits of cotreatment with a hepcidin mimetic peptide plus the rusfertide analogue PN-23114 (Protagonist Therapeutics Inc.) at 7.5 mg/kg t.i.w. and phlebotomy in a murine model of HH.
Investigators from Cerevance Inc. have reported the discovery and preclinical characterization of a novel tandem pore domain halothane-inhibited K+ channel 1 (THIK-1) inhibitor, C-101248, being developed for the treatment of neuroinflammation in Alzheimer’s disease (AD). NETSseq and histological analysis revealed that THIK-1 expression was up-regulated in microglia from different cortical regions of AD donors compared with aged matched nondemented control brains.
The archetypal UbiB protein COQ8 has human homologues COQ8A and COQ8B, both with well-established connection to human disease, with inactivating mutations in COQ8A resulting in autosomal recessive cerebellar ataxia. Researchers from the University of Wisconsin-Madison and affiliated organizations have now recently reported the discovery of small-molecule inhibitors of COQ8A.
Researchers from Nalo Therapeutics Inc. presented the discovery and preclinical evaluation of a novel orally bioavailable and brain-penetrant epidermal growth factor receptor (EGFR) inhibitor, NX-019, being developed as a potential therapeutic agent to treat EGFR-mutant solid tumors.
Researchers from Suven Life Sciences Ltd. presented the discovery and preclinical characterization of a novel muscarinic acetylcholine M4 receptor positive allosteric modulator (PAM), SUVN-L1305022.
Researchers from Cerevel Therapeutics LLC presented data from a study that aimed to evaluate preclinical antipsychotic properties of M4 agonism while minimizing off-target side effects using novel muscarinic acetylcholine M4 receptor full and partial agonists, CV-0000042 (CVL-042) and CV-0000071, respectively.
Maze Therapeutics Inc. recently presented data from preclinical studies of a small-molecule APOL1 pore function inhibitor, MZ-301, describing the compound’s in vitro and in vivo activity. APOL1 G1 and G2 genetic variants are associated with an increased risk of progressive kidney diseases in African ancestry people. There are no APOL1-targeted therapies addressing the underlying driver of these diseases.