August’s Molecules of the Month include Kannalife Sciences’ GPR55 antagonist for chemotherapy-induced neuropathic pain and Boehringer Ingelheim’s zwitterionic inhibitor of KHK for metabolic disorders. We also feature bomedemstat, Merck’s irreversible LSD1 inhibitor, which has entered a pivotal Ph. III trial. Other notable molecules from August include a small peptide inhibitor of the Fas receptor from ONL Therapeutics and Boehringer Ingelheim’s PDE4B inhibitor with the potential to treat IPF.
You can read more about the compounds that made our August 2024 Molecules of the Month list and check out recent articles for each, linked below:
KLS-13019 – A CBD (cannabidiol) analogue and GPR55 (G protein-coupled receptor 55) antagonist from Kannalife Sciences, which shows promise as a novel therapeutic for neuropathic pain, particularly chemotherapy-induced neuropathic pain. In rat models, KLS-13019 demonstrated dose-dependent reversal of mechanical and cold allodynia after both paclitaxel and oxaliplatin exposure. It was effective in both acute and chronic dosing paradigms, fully reversing allodynia and even preventing its development when co-administered with paclitaxel. These results suggest that KLS-13019 offers a potent and durable treatment option for neuropathic pain, addressing the need for safer and more effective alternatives to opioids.
BI-9787 – A potent zwitterionic inhibitor of KHK (ketohexokinase) designed to explore the therapeutic potential of KHK inhibition in metabolic disorders like diabetes, non-alcoholic fatty liver disease, and NASH (non-alcoholic steatohepatitis). Incorporating a carboxylic acid moiety ensures high target selectivity, while its chameleonic properties contribute to excellent permeability and favorable oral pharmacokinetics in rats. Identified through ligand-based virtual screening, BI-9787 serves as a high-quality in vitro and in vivo tool compound for studying fructose metabolism and its role in disease progression.
compound 20 – A galactose-based monosaccharide Gal-3 (Galectin-3) inhibitor from Bristol Myers Squibb that shows potential in targeting fibrotic diseases. Galectins are a relatively underexplored target class, despite academic research suggesting potential roles in a variety of difficult-to-treat diseases, including (IPF) idiopathic pulmonary fibrosis with Galecto’s GB0139 (clinical development discontinued) and GB1211 being two of the most clinically advanced Gal-3 targeting drugs. Structurally, compound 20 features a 2-methyl-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione moiety, which induces thermodynamically stable atropisomers along with steric interactions. X-ray structures of compound 20 (the eutomer) provided key insights into its binding mode, contrasting with compound 21 (the distomer), where a key halogen bonding σ-hole interaction of 3-chloro with carbonyl oxygen of Gly182 led to a loss in potency. Both compound 20 and its analog, compound 15, demonstrated suitable oral bioavailability in mouse pharmacokinetic studies, positioning them for further in vivo evaluation as Gal-3 inhibitors for fibrosis treatment.
compound 8 – A dual 5-HT2A and 5-HT2C receptor inverse agonist developed to address the limitations of pimavanserin, a 5-HT2A receptor inverse agonist with minimal 5-HT2C receptor affinity and no dopamine D2 receptor affinity, in treating dementia-related psychosis. By introducing a spirocyclopropyl group to enhance 5-HT2C affinity and optimizing lipophilicity, compound 8 achieved balanced dual potency, metabolic stability, and minimal hERG inhibition. In preclinical models, compound 8 demonstrated significant antipsychotic efficacy by targeting both 5-HT2A and 5-HT2C receptors, showing promise as a more effective treatment for psychosis in dementia.
bomedemstat (MK-3543, IMG-7289) – Merck’s irreversible LSD1 (lysine-specific demethylase 1) inhibitor, has entered a pivotal Ph. III clinical trial (NCT06456346) for the treatment of ET (essential thrombocythemia). This randomized, double-blind trial compares bomedemstat to hydroxyurea in patients who have not received prior cytoreductive therapy. Discovered by Imago BioSciences and subsequently acquired by Merck in 2022, bomedemstat targets LSD1 to regulate hematopoietic stem cell proliferation and differentiation and is also being evaluated in other trials for MPNs (myeloproliferative neoplasms) such as MF (myelofibrosis) and PV (polycythemia vera). It holds FDA Orphan Drug and Fast Track designations for ET and MF.
BAY-2925976 – A highly selective ARα2C (alpha-2c adrenergic receptor) antagonist with improved brain penetration and efficacy, aimed at treating OSA (obstructive sleep apnea) by stabilizing upper airways and preventing collapse through increased hypoglossal motoneuron activity. The structure and discovery story of this molecule was recently presented at the ACS Fall 2024 First Time Disclosure session in Denver.
Xanamem® – Actinogen Medical's Xanamem®, a cortisol-blocking drug targeting the 11β-HSD1 (11β-hydroxysteroid dehydrogenase) enzyme, recently failed to improve cognitive function in patients with major depressive disorder but showed promise in secondary endpoints related to depression. In the Ph. II XanaCIDD trial (NCT05657691), patients receiving 10 mg of Xanamem® over 10 weeks had a 50% higher rate of depression remission compared to placebo and reported less severe depressive symptoms. This resulted in a 90% rise in Actinogen’s stock price, after an initial 60% decline when cognitive function endpoints were missed. Xanamem® is also in a Ph. II trial (NCT06125951) for Alzheimer’s disease, where its ability to cross the blood-brain barrier and inhibit 11β-HSD1 by 50% is expected to reduce brain cortisol levels more effectively than previous systemic inhibitors.
nerandomilast (BI 1015550) – Boehringer Ingelheim’s PDE4B (phosphodiesterase 4) inhibitor with demonstrated clinical potential in treating IPF (idiopathic pulmonary fibrosis) that was disclosed at the 2023 ACS Spring meeting. PDE4 has been explored as a target since the 1970s, and we’ve covered other inhibitors in this space a few times, including the inhaled compound CHF-6001, and the topical compounds PF-07038124 and LEO 39652. It is well-known that pan-PDE4 inhibitors, like roflumilast and apremilast, have dose-limiting GI side effects (including nausea and vomiting), but this molecule, which has been in the clinic since ~2012, appears to be well-tolerated. In a newly published report, nerandomilast improved lung function and normalized most transcripts deregulated by bleomycin treatment in a rat model of pulmonary fibrosis. Transcriptomic analysis revealed significant overlap with human IPF data, particularly affecting mesenchymal, epithelial, and endothelial cell populations. In vitro studies using human epithelial cells confirmed nerandomilast's ability to inhibit disease-related biomarkers in a concentration-dependent manner. These findings highlight nerandomilast's anti-inflammatory and antifibrotic mechanisms and provide new insights into its molecular targets in lung fibrosis.
vactosertib – An orally bioavailable TGFβ (transforming growth factor-β) type I receptor kinase inhibitor, has demonstrated safety, tolerability, and clinical efficacy in combination with pomalidomide in a Ph. Ib trial (NCT03143985) for RRMM (relapsed and/or refractory multiple myeloma) patients. The combination reduced tumor cell viability, reinvigorated CD8+ T-cell activity, and overcame immunosuppressive challenges within the tumor microenvironment. Exploratory analyses revealed a reduction in TGFβ levels and PD-1 expression on CD8+ T-cells in patient bone marrow, with promising progression-free survival outcomes. Vactosertib shows potential as a strategy to enhance immunotherapeutic responses in heavily pretreated RRMM patients.
ONL1204 – ONL Therapeutics' small peptide inhibitor of the Fas receptor, has shown promise as a therapeutic approach for IRD (inherited retinal degeneration) by targeting a mutation-independent, shared pathophysiologic mechanism of cell death and inflammation. In both rd10 and P23H mouse models, intravitreal injections of ONL1204 led to reduced photoreceptor cell death, decreased caspase 8 activity, improved photoreceptor survival, and enhanced retinal function compared to vehicle-treated eyes. This suggests that ONL1204's inhibition of Fas-mediated pathways may provide a broad therapeutic strategy for IRD patients, regardless of genetic mutation. ONL1204 has recently completed a Ph. II trial (NCT05730218) in subjects with macula-off rhegmatogenous retinal detachment.
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