Cachexia is a complicated metabolic syndrome mainly associated with cancers, characterized by extreme weight loss and muscle wasting. It is a debilitating condition that negatively affects prognosis and survival. However, there is currently no effective pharmacological intervention that can reverse body weight loss and improve physical performance in patients with cachexia. Growth differentiation factor 15 (GDF15) can suppress appetite and regulate energy balance through binding to glial cell-derived neurotrophic factor receptor alpha-like (GFRAL). In order to develop a novel, effective treatment for cachexia, we generated a GDF15-targeting VHH nanobody, GB18-06, that was able to bind GDF15 with high affinity. In vitro, GB18-06 potently inhibited the GDF15-GFRAL signaling pathway, leading to a reduction of downstream ERK and AKT phosphorylation levels; in vivo, GB18-06 alleviated weight loss (>20%) in cancer and chemotherapy-induced cachexia models in mice. Compared with the control (phosphate-buffered saline) group, the ambulatory activity of mice in the GB18-06-treated group also increased 77%. Furthermore, GB18-06 exhibited desirable pharmacokinetic properties and an excellent developability profile. Our study has demonstrated a means of developing targeted treatment for cachexia with high efficacy, potentially leading to improved clinical outcomes and quality of life for patients with cachexia.

First-generation KRAS G12C inhibitors, such as sotorasib and adagrasib, are limited by the depth and duration of clinical responses. One potential explanation for their modest clinical activity is the dynamic "cycling" of KRAS between its guanosine diphosphate (GDP)- and guanosine triphosphate (GTP)-bound states, raising controversy about whether targeting the GDP-bound form can fully block this oncogenic driver. We herein report that D3S-001, a next-generation GDP-bound G12C inhibitor with faster target engagement (TE) kinetics, depletes cellular active KRAS G12C at nanomolar concentrations. In the presence of growth factors, such as epithelial growth factor and hepatocyte growth factor, the ability of sotorasib and adagrasib to inhibit KRAS was compromised whereas the TE kinetics of D3S-001 was nearly unaffected, a unique feature differentiating D3S-001 from other GDP-bound G12C inhibitors. Furthermore, the high covalent potency and cellular TE efficiency of D3S-001 contributed to robust antitumor activity preclinically and translated into promising clinical efficacy in an ongoing phase 1 trial (NCT05410145). Significance: The kinetic study presented in this work unveils, for the first time, that a GDP-bound conformation-selective KRAS G12C inhibitor can potentially deplete cellular active KRAS in the presence of growth factors and offers new insights into the critical features that drive preclinical and clinical efficacy for this class of drugs.
©2024 The Authors; Published by the American Association for Cancer Research.

Dopamine D3 receptor (D3R) is implicated in multiple psychotic symptoms. Increasing the D3R selectivity over dopamine D2 receptor (D2R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D3R selective ligands. Through a structure-based virtual screen, ZLG-25 (D3R Ki = 685 nmol/L; D2R Ki > 10,000 nmol/L) was identified as a novel D3R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D3R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD3R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.
© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

D-1553 is a small molecule inhibitor selectively targeting KRASG12C and currently in phase II clinical trials. Here, we report the preclinical data demonstrating antitumor activity of D-1553. Potency and specificity of D-1553 in inhibiting GDP-bound KRASG12C mutation were determined by thermal shift assay and KRASG12C -coupled nucleotide exchange assay. In vitro and in vivo antitumor activity of D-1553 alone or in combination with other therapies were evaluated in KRASG12C mutated cancer cells and xenograft models. D-1553 showed selective and potent activity against mutated GDP-bound KRASG12C protein. D-1553 selectively inhibited ERK phosphorylation in NCI-H358 cells harboring KRASG12C mutation. Compared to the KRAS WT and KRASG12D cell lines, D-1553 selectively inhibited cell viability in multiple KRASG12C cell lines, and the potency was slightly superior to sotorasib and adagrasib. In a panel of xenograft tumor models, D-1553, given orally, showed partial or complete tumor regression. The combination of D-1553 with chemotherapy, MEK inhibitor, or SHP2 inhibitor showed stronger potency on tumor growth inhibition or regression compared to D-1553 alone. These findings support the clinical evaluation of D-1553 as an efficacious drug candidate, both as a single agent or in combination, for patients with solid tumors harboring KRASG12C mutation.
© 2023 InventisBio Co., Ltd and The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

All types of dementia, including Alzheimer's disease, are debilitating neurodegenerative conditions marked by compromised cognitive function for which there are few effective treatments. Positive modulation of hepatocyte growth factor (HGF)/MET, a critical neurotrophic signaling system, may promote neuronal health and function, thereby addressing neurodegeneration in dementia. Here, we evaluate a series of novel small molecules for their ability to (1) positively modulate HGF/MET activity, (2) induce neurotrophic changes and protect against neurotoxic insults in primary neuron culture, (3) promote anti-inflammatory effects in vitro and in vivo, and (4) reverse cognitive deficits in animal models of dementia. Through screening studies, the compound now known as fosgonimeton-active metabolite (fosgo-AM) was identified by use of immunocytochemistry to be the most potent positive modulator of HGF/MET and was selected for further testing. Primary hippocampal neurons treated with fosgo-AM showed enhanced synaptogenesis and neurite outgrowth, supporting the neurotrophic effects of positive modulators of HGF/MET. Additionally, fosgo-AM protected against neurotoxic insults in primary cortical neuron cultures. In vivo, treatment with fosgo-AM rescued cognitive deficits in the rat scopolamine amnesia model of dementia. Although fosgo-AM demonstrated several procognitive effects in vitro and in vivo, a prodrug strategy was used to enhance the pharmacological properties of fosgo-AM, resulting in the development of fosgonimeton (ATH-1017). The effect of fosgonimeton on cognition was confirmed in a lipopolysaccharide (LPS)-induced neuroinflammatory mouse model of dementia. Together, the results of these studies support the potential of positive modulators of HGF/MET to be used as novel therapeutics and suggest the drug candidate fosgonimeton might protect against neurodegeneration and be therapeutic in the management of Alzheimer's disease and other types of dementia.
© 2022. The Author(s).