Drug Repurposing Patent Applications January–March 2023

A VETERINARY ANTIBIOTIC FOR ALLERGIC DISEASES

WO/2023/277761, New Use of Monensin (Inventors: Pejler G, Paivandy A, Maccarana M, Adner M; applicants: Sweden; published: January 5, 2023).

Monensin A, a lipophilic polyether antibiotic isolated from Streptomyces cinnamonensis, is used extensively in cattle and poultry industries to prevent coccidiosis. ¹ Like other compounds of this type, it is an Na⁺/H⁺ ionophore and, therefore, has a variety of biological properties ² ; it is among the antibiotics that have shown indications of promise in many types of solid tumors. ³ In a search for novel agents that selectively reduce the viability of mouse bone marrow-derived mast cells, the inventors screened a drug library using reduction of resazurin to a fluorescent product as readout.

Only monensin was more cytotoxic to mast cells than to either the primary human fibroblast cell line HFL-1, primary human small airways epithelial cells, or the human cancer epithelial HEK-293 cell line. Immature human mast cell lines (LUVA, HMC-1) and fully mature skin mast cells (hskinMC) also showed considerable sensitivity to monensin, which caused mainly caspase-independent apoptosis through a mechanism involving granule permeabilization but without inducing mast cell activation. This was observed at nanomolar concentrations of meonensin, orders of magnitude lower than those that had been shown to prevent histamine release from activated mast cells before itself becoming a secretagogue upon prolonged incubation. ⁴

The acidity of the granules was found to be a prerequisite for optimal responses. In tracheal tissues isolated from house dust mite-sensitized guinea pigs, monensin (1 or 10 mM) abrogated airway reactivity upon exposure to the allergen. Eosinophils showed approximately equal sensitivity to monensin as did mast cells. All this could make it an interesting agent to treat allergic type I hypersensitivity conditions such as asthma, rhinitis, conjunctivitis, dermatitis, anaphylaxis, or urticaria: also mastocytosis and mast cell activation syndrome, as well as eosinophilia.—For the peer review companion article see Maccarana et al. ⁵

A RETRACTED WEIGHT LOSS DRUG FOR DISTURBED BREATHING

WO/2023/278597, 5-HT_2c Agonists for Use in Treating Conditions Associated with Central Hypoventilation (Inventors: Taranto-Montemurro L, Farkas R, Miller LG; applicant: Apnimed, Inc., Cambridge, Massachusetts, USA; published: January 5, 2023).

Obesity hypoventilation syndrome (OHS) is a condition in which patients with a body mass index ≥30 kg/m² and sleep disordered breathing fail to breathe properly even during daytime, resulting in low blood oxygen saturation and hypercapnia (CO₂ levels ≥45 mmHg). Without the only curative intervention (extreme weight loss) it is associated with heart failure, coronary disease, and pulmonary hypertension. ⁶ No pharmacological treatments of OHS have been explored or approved to date.

Because serotonin can activate hypoglossal motoneurons through central 5-HT_2C (but not 5-HT_2A) receptors, especially during wakefulness, ⁷ the inventors conducted crossover pilot trial including obstructive sleep apnea (OSA) patients who were administered 15 mg of the 5-HT_2C agonist lorcaserin (a weight loss drug that the manufacturer, Eisai Pharmaceuticals, withdrew because of an increased cancer risk) or placebo in random order before bedtime for one night. Ventilation during non-rapid eye movement sleep increased substantially with lorcaserin.

The problem is that this is only indirect evidence: OSA is primarily a peripheral phenomenon (caused by upper airway collapse during deep sleep) in the great majority of cases, and although central sleep apnea also exists, ⁸ it has brainstem or neuromuscular etiology, and can be nonhypercapnic. However, because OHS and OSA are frequently comorbid in extremely obese people, OHS patients might also profit from lorcaserin.

This patent application claims not only lorcaserin and other 5-HT_2C agonists (such as vabicaserin, dropped from development because of psychosis and depression in 2010) but also coadministration of acetazolamide: carbonic anhydrase inhibitors have been shown to decrease bicarbonate concentration and increase CO₂ response in OHS ⁹ —another indication of repurposing potential because this old drug was primarily used in glaucoma.—Note WO/2023/006993 (discussed hereunder in this contribution) claiming a repurposed Hsp90 inhibitor for the rare congenital form of central hypoventilation.

NICOTINE AND VARENICLINE MIGHT CONTROL MYOPIA

WO/2023/279162, Methods of Treatment and Inhibition (Inventor: Ashby RS; applicant: University of Canberra, Bruce, Australia; published: January 12, 2023).

Muscarinic acetylcholine receptor antagonists, such as atropine and the more subtype selective pirenzepine, are useful for the treatment and prevention of high myopia, which suggests that hyperactivity of the retinal cholinergic system may underlie the excessive axial elongation of the eye that causes shortsightedness. However, retinal acetylcholine and choline content are not significantly different in myopic and control eyes of animal models, ¹⁰ and it has been suggested that these drugs actually exert their effect through α2A-adrenoceptors, ultimately stimulating dopamine release. ^11,12

The present invention is predicated on the discovery that nicotine (15 mM eye drops or injected intravitreally) is effective in the classic chick model of form-deprivation myopia: ANOVA indicated a significant treatment effect [refraction F(3,21) = 3.758, p = 0.03; axial length F(3,21) = 2.664, p = 0.04]. It is likely that other nicotinic acetylcholine receptor (nAChR) agonists, such as the smoking cessation drug varenicline that is also claimed (without data being disclosed), could be comparably effective.

This would be consistent with dopamine being the ultimate effector: nAChRs expressed on dopaminergic neurons are well known to modulate neurotransmitter release. A recent article, published a few months after this invention's July 2021 priority date, confirmed that nicotinic agonists may represent a novel and more targeted approach for the cholinergic control of myopia as they are unlikely to cause the anterior segment side effects associated with muscarinic treatment, but also demonstrated that retinal dopamine release is not required for atropine's antimyopic effects. ¹³ The mechanistic background is still not completely clear.

A T CELL LYMPHOMA DRUG FINDS USES IN NEUROLOGY

WO/2023/288110, Romidepsin as a Therapeutic Agent for Nerve-Injury Induced Neuropathic Pain and Spasticity (Inventor: Tan A; applicants: The United States Government as represented by the Department of Veterans Affairs, Washington, District of Columbia, USA; published: January 19, 2023).

Romidepsin, a depsipeptide, is an intravenously administered histone deacetylase inhibitor and antineoplastic agent that is approved for use in refractory or relapsed cutaneous and peripheral T cell lymphomas, although results in recently published clinical studies have varied. ^14,15 As an epigenetic agent that partially unwinds chromosomes, and enhances histone acetylation, as well as the acetylation of other nuclear or cytoplasmic proteins, romidepsin has also found interesting applications that are far outside the cancer field (but related in their pathways because associated genes are also enriched for chromatin remodelers): reactivation of latent human immunodeficiency virus for eradication therapy, ¹⁶ and reversing the social deficits associated with autism spectrum disorder. ¹⁷

Because bioavailable concentrations of romidepsin (0.1 nM) significantly inhibit Pak1, ¹⁸ an Rac1 activated kinase that has been implicated in mechanisms underlying pain, ¹⁹ and is required for the dendritic spine dysgenesis that can also result in spasticity, ²⁰ the inventors decided to look for its efficacy in the respective animal models. Romidepsin was administered to C57BL/6 mice with a transection-type peripheral nerve injury as an intraperitoneal injection for 5 consecutive days postinjury (0.25 mg/kg once per day for 5 days), which resulted in a significant decrease in mechanical-evoked pain.

Evoked H-reflex recordings illustrate a partial reduction in spasticity (increased slope) with romidepsin treatment (three intrathecal injections 2 weeks after injury or sham surgery) in a spinal cord injury model expressing fluorescent green fluorescent protein driven by the neuron-specific thymus cell antigen-1 promotor (p < 0.05). Romidepsin administration also led to a significant increase in histone H3 density, which is a marker for deacetylation within the tissues of the spinal cord.

SUBNANOMOLAR AMOUNTS OF COVALENTLY BINDING SERINE PROTEASE INHIBITORS BOOST A NONCOVALENT ONE AGAINST SARS COV-2 ENTRY

WO/2023/001634, Pharmaceutical Composition for Treating COVID-19 Comprising Otamixaban and at Least One of Camostat and Nafamostat (Inventors: Hempel T, Elez K, Raich L, Noé F, Krüger N, Pöhlmann S; applicants: Freie Universität Berlin, Berlin, Germany; Deutsches Primatenzentrum GmbH–Leibniz-Institut für Primatenforschung, Göttingen, Germany; published: January 26, 2023).

Two major host factors contribute to the virulence of SARS-CoV-2: angiotensin converting enzyme 2 (Ace-2, the “hijacked” viral receptor) and transmembrane protease serine 2 (Tmprss-2, which cleaves the complex formed by the viral spike protein and Ace-2). ²¹

The inventors found otamixaban, an investigational direct Factor Xa inhibitor anticoagulant with a reversible and noncovalent mode of action that was discontinued from development by Sanofi after a failed phase 3 clinical trial, to be a weak inhibitor of Tmprss-2 with an IC₅₀ value that is two to three orders of magnitude above that of the more established covalent serine protease inhibitors camostat (approved in Japan for the treatment of chronic pancreatitis and postoperative reflux esophagitis) and nafamostat (used as a fast-acting anticoagulant during hemodialysis): both of which had been discovered through Tmprss-2 binding studies using molecular modeling and docking. ^22,23

However, strong synergistic effects were observed when otamixaban was combined with either of these, even at very small molecular ratios (around 1:5,000). It is sufficient if camostat or nafamostat are present in the nanomolar or subnanomolar range to improve the IC₅₀ of otamixaban massively, from 18.7 μM to ∼0.74 μM. Analysis of molecular dynamic simulations revealed that otamixaban binds Tmprss-2 with multiple metastable binding modes. Given that all three drugs bind to the S1 pocket of Tmprss-2, it seems unlikely that they have a cooperative mechanism toward the same target. Instead it could be explained by a yet-unidentified secondary target.—For the peer review companion article, see Hempel et al. ²⁴

ONE OF THE NEWEST ANTIPSYCHOTICS IS A SURVIVIN INHIBITOR

WO/2023/006954, Asenapine for Use in Cancer (Inventors: Soto Cerrato V, Korrodi Mineiro Marques Gregório L, Martínez García D, Pérez Tomás RE, et al.; applicants: Universitat de Barcelona, Barcelona, Spain; Fundació Institut d'Investigació Biomèdica de Bellvitge—IDIBELL, Barcelona, Spain; Universidad de Burgos, Burgos, Spain; Nostrum Biodiscovery, S. L., Barcelona, Spain; published: February 2, 2023).

Asenapine is not among the many antipsychotics for which experimental data concerning antiproliferative effects had been reported so far. ²⁵ Actually, WO/2016/062285 lists asenapine among the tested drugs without any inhibitory effects on multiple cancer cell lines. The present document reports quite opposite findings: asenapine reduced viability in human lung adenocarcinoma (A549) and colon adenocarcinoma (SW620) cancer cell lines with statistical significance, and also showed effects against pediatric neuroblastoma (LAN-1), pediatric sarcoma (RD), and glioblastoma (U87) cell lines, in the same range of efficacy as other approved chemotherapeutics such as cisplatin.

Surface plasmon resonance assays were designed to monitor the interaction between survivin (tagged with calmodulin) and asenapine, and a subcutaneous LLC1 mouse xenograft tumor model was used to determine in vivo efficacy. When tumors reached ∼40 mm³, tumor-bearing mice were treated with vehicle or 10 mg/kg of asenapine maleate once a day on a 5 days on/2 days off schedule for 22 days, which resulted in a tumor volume reduction by about one-third at endpoint.

For the combination efficacy study, asenapine maleate (5 mg/kg, 5 days per week) and cisplatin (3 mg/kg on days 0, 3, and 6) were administered, also intraperitoneally, and showed limited synergism. The inventors do not say what prompted them to look for survivin inhibition, but it would seem that asenapine belongs in this class, and also sensitizes cancer cells to cisplatin.

ONE MORE POTENTIAL USE FOR HSP90 INHIBITORS

WO/2023/006993, Fused Amino Pyridine or Pyrimidine Derivatives for the Treatment of Congenital Central Hypoventilation Syndrome (Inventors: Proton de la Chápelle X, Beckouche N, Annereau J-P, Briseno-Roa L, Rayar A, Pineau N; applicants: AtmosR, Fuveau, France; Medetia S.A.S., Paris, France; Assistance Publique–Hôpitaux de Paris, Paris, France; Universite Paris Cité, Paris, France; Fondation Imagine, Paris, France; published: February 2, 2023).

Although WO/2023/278597 (already discussed) has claimed 5-HT_2C receptor agonists for the treatment of OHS (distinct from obesity-related sleep apnea, although both are frequently comorbid), there also is “Ondine's curse,” a rare congenital manifestation of autonomic respiratory dysregulation requiring life-long respiratory support; it is caused by heterozygous in-frame duplications in the PHOX2B gene. ²⁶ There is no pharmacological treatment; the patients' medullary respiratory neurons may be incapable of responding to established respiratory stimulants. ²⁷

One potential opportunity is that activation of the heat shock response by the Hsp90 inhibitor geldanamycin prevents formation and induces clearance of dysfunctional Phox2b protein aggregates, ultimately rescuing its ability to transactivate the dopamine beta-hydroxylase promoter ²⁸ ; this enzyme converts dopamine to noradrenaline, an important effector in respiration. One of the Hsp90 inhibitors claimed by the inventors is CUDC 305 (previously Debio-0932), a candidate discontinued for cancer but probably still under investigation for dermatological indications.

In a fluorescence recovery after photobleaching assay with HeLa cells transfected with plasmid expressing mutant Phox2b-5Ala, mobility of this protein was significantly increased. In an animal model of congenital central hypoventilation syndrome (newborn Egr2^Cre/+Phox2b^27ala/+ mice), CUDC 305 treatment led to a statistically significant increase in the response to metabolic acidosis after 7 h of treatment.

AN OLD MUSCLE RELAXANT, SK CHANNELS, AND MEMORY

WO/2023/009397, Novel Drug Treatment of Cognitive Impairments Associated with Schizophrenia (Inventors: Rice CA, Stackman RW; applicant: Florida Atlantic University Board of Trustees, Boca Raton, Florida, USA; published: February 2, 2023).

Chlorzoxazone is a centrally acting and sedating spasmolytic that has been in use for several decades the United States and elsewhere. It was identified and developed as the active keto metabolite of zoxazolamine, an even older muscle relaxant that was withdrawn from the market because of hepatotoxicity issues. Among its targets are the intermediate-conductance Ca²⁺ activated K⁺ channel, IK1 and the large conductance channel BK(Ca) but the functionally most important one is the small-conductance channel SK2, a close IK1 homolog. ²⁹

Chlorzoxazone improves cognitive deficits and reduces hippocampal neuronal death in APP/PS1 mice, a dual transgenic model of Alzheimer disease. ³⁰ In this light, it might not seem particularly surprising what the inventors have shown in their first set of experiments: chlorzoxazone (5 mg/kg i.p.) improved object recognition in ketamine-impaired mice (a model of psychosis), almost completely rescuing their memory retention.

More interestingly, results in the trace fear memory test (a paradigm to model aversive learning, where predictors and aversive outcomes are separated in time) were borderline significant: mice treated with chlorzoxazone exhibited impaired freezing behavior (i.e., less fear) compared with controls when confronted with the original stimulus, which is consistent with previous studies demonstrating that activation of SK channels impairs hippocampal-dependent memory in fear conditioning and fear extinction protocols. This illustrates the meta phenomenon nature of cognition, and sheds light on how the etiology and mechanisms of memory impairment in Alzheimer's disease and schizophrenia differ.

A COMMON THIRD-GENERATION ANTIHISTAMINE FOR AMYOTROPHIC LATERAL SCLEROSIS

WO/2023/019823, Use of Desloratadine and Salt Thereof in Preparation of Drug for Treating Neurodegenerative Diseases Related to Motor Dysfunction (Inventors: Shen X, Wang J, Huang Y, Lu J; applicant: Nanjing University of Chinese Medicine, Nanjing, China; published: February 23, 2023).

Desloratadine, the active metabolite of loratadine and an inverse agonist at H₁ histamine receptors like its less potent parent compound, ³¹ has largely replaced loratadine as an antiallergic drug because it is essentially peripherally restricted, ³² which avoids the sedation that results from central H₁ receptor blockade by earlier antihistamines. However, passage of desloratadine across the human blood–brain barrier might occur to some degree, at least under certain circumstances, ³³ and the inventors have reported earlier that it ameliorates Alzheimer's disease pathology in double-transgenic APP/PS1 mice, acting as a selective 5HT_2A receptors antagonist and repressing neuroinflammation through the cAMP/PKA/CREB/Sirt1 pathway.

In the present document they extend their research to amyotrophic lateral sclerosis, showing that desloratadine (20 mg/kg per day) is also effective in the SOD1-G93A mouse model, postponing time to motor symptom onset and extending survival (both p < 0.05), ameliorating the decrease in grip strength of all four limbs, improving gait abnormalities, and also dyskinesia in the rotarod paradigm (all p > 0.01 and better). There is no mention of any pretreatment that might have permeabilized the blood–brain barrier.

A HUGE BIOINFORMATICS-DRIVEN REPURPOSING EFFORT FOR NONSMALL CELL LUNG CANCER

WO/2023/023592, Repurposing Drugs for Non-Small Cell Lung Cancer (Inventor: Guo NL; applicants: West Virginia University Boards of Governors on behalf of West Virginia University, Morgantown, West Virginia, USA; published: February 23, 2023).

This patent application discloses a massive effort at batch repurposing based on complex biomarkers and a combination of omics: the antibiotics anisomycin, puromycin, and aztreonam; the veterinary antiparasitic ivermectin and the antifungal trichostatin A; the alcohol deterrent disulfiram, the kinase inhibitors dasatinib and lestaurtinib; the antipsychotic penfluridol; and homosalate (a common component of sunscreens) are claimed. A Boolean implication network scheme is disclosed that models copy number variations and gene expression profiles in nonsmall cell lung cancer (NSCLC) tumors (n = 371) to decipher molecular networks for CD27, and dissect those involving CD27, PD1, and PDL1.

Significantly enriched cytobands, pathways, and gene families were analyzed for the constructed CD27 networks. Based on this network proliferation, genes were identified from CRISPR-Cas9 (n = 78) and RNAi (n = 92) screening data; prognostic genes were selected and validated in NSCLC tumors (n = 1163). Confirmed genes were examined for their association with chemotherapy in the Cancer Cell Line Encyclopedia NSCLC panel (n = 117) and radiotherapy in The Cancer Genome Atlas patient tumors (n = 966).

The growth inhibitory activity of 4,518 drugs was quantified in 578 human cancer cell lines using the PRISM molecular barcoding and multiplexed screening method, and response was categorized corresponding to the RECIST 1.1 system for tumors (i.e., complete response, partial response, and stable disease/disease progression). This resulted in the mentioned claimed drugs, plus FK 888 (tachykinin NK1 receptor antagonist) and piperlongumine (a pepper alkaloid).

DIABETES, WEIGHT LOSS, AND LONG COVID SYNDROME

WO/2023/028554, GLP-1R Agonists for Use in a Treatment of Neurological Impairment Associated with Viral Infection (Inventors: Bell AC, Roschke V, Karanth S, Lee S; applicant: Neuraly, Inc., Gaithersburg, Maryland, USA; published: March 2, 2023).

If symptoms such as fatigue, shortness of breath, trouble sleeping, “brain fog,” cognitive dysfunction, or memory loss persist 6 months or longer after Covid-19 has resolved, the diagnosis is post-Covid syndrome (PCD), colloquially called “Long Covid” or “Long Hauler Syndrome.” ³⁴ Animal data suggest that in some patients, SARS CoV-2 causes microglial activation that can outlast direct infection damage. ³⁵ The GLP-1 receptor is expressed on microglia but only minimally on neurons, and considering the roles of microglia and astrocytes in brain inflammatory responses, cognition, and neurodegeneration, they are targets for therapeutic strategies against latent neurological manifestations of Alzheimer's and Parkinson's diseases ³⁶ and could be equally valuable in PCD.

This document claims long-acting glucagon-like peptide 1 receptor agonists, such as albuglutide, duloglutide, or PEGylated exenatide (which readily traverses the blood–brain barrier, and is preferred). Short acting GLP-1R agonists may also be effective if administered more frequently. To determine the efficacy of NLY01 (a PEGylated exenatide disclosed in WO/2013/002580) on microglial activation in vivo, 3-month-old C57BL6 mice were given a unilateral intrastriatal stereotaxic injection of recombinant α-synuclein preformed fibrils (5 pg/μL) to stimulate microglial activation.

After 1 month, NLY01 was delivered subcutaneously (3 mg/kg, twice a week) for 5 months. Mice were perfused and brain tissues collected to allow analysis of activated microglia and cytokine levels after treatment. Synuclein-induced production of proinflammatory cytokines and reduced neural function were almost normalized. NLY01 had already been shown to reduce retinal inflammation and ganglion cell death in a mouse model of glaucoma. ³⁷

A FORMER ANORECTIC TREATS DRAVET SYNDROME BY AN UNEXPECTED MECHANISM

WO/2023/034115, Fenfluramine for Treatment of Demyelinating Diseases and Conditions (Inventors: Cha JC-E, Reeder TC; applicant: Zogenix International Ltd., Berkshire, United Kingdom; published: March 9, 2023).

Fenfluramine, a serotonergic agent and sigma receptor modulator, is a case of successful repurposing after market withdrawal: originally developed and approved as a weight loss drug (alone and in combination with phentermine), it was discontinued in the late 1990s because of an association with cardiac valvulopathy, but was reintroduced in 2020, under controlled access programs and at reduced doses, as a medication for Dravet and Lennox-Gastaut syndromes, two forms of childhood epilepsy that are almost intractable otherwise. ³⁸

The antiseizure mechanism had not been elucidated but was expected to result from a combination of the known fenfluramine targets. ³⁹ Seeking different explanations, the inventors have found that fenfluramine binds RNF-43, a membrane-bound RING finger protein and ubiquitin ligase that downregulates both Wnt/p-catenin classical signaling and noncanonical Wnt signaling by distinct mechanisms. ⁴⁰ Fenfluramine enhances RNF43's ability to downregulate the effects of high Wnt signaling on oligodendrocyte precursor cells, especially those in demyelinated white matter.

Studies were conducted in treated and untreated mice having an SCN1A gene mutation, which produces a murine model of Dravet syndrome. Activation of microglia (as judged by an unambiguous increase in microglial body size, ramification thickness, and length when microglia assume a rod-shaped form) and myelin pathology and damage were significantly reduced. This is also being studied in a mouse model of chronic hypoxia, which can cause myelination abnormalities.

FROM SLEEPING SICKNESS TO CANCER COAGULOPATHY

WO/2023/041831, New Colorectal Cancer Treatment (Inventors: Pérez Sánchez H, Peña García J, Carmona Bayonas A, Rodenas Bleda MDC, et al.; applicants: Fundacion Universitaria San Antonio, Guadalupe, Spain; Instituto Murciano de Investigación Biosanitaria, El Palmar, Spain; published: March 23, 2023).

Driven by antiangiogenic monoclonal antibodies, treatment of colorectal cancer has made great strides during the past two decades, which could explain that drug repurposing activity for this common type of solid tumor is not particularly high. Spanish inventors have nevertheless found an interesting candidate: suramin, the first drug developed to treat African trypanosomiasis. In the present invention, the drug is not intended to treat the cancer as such but rather to reduce its invasiveness, and to prevent or treat development of venous thromboembolic events, a common problem in digestive tumors. ⁴¹

The basis of this is that in the course of a high-throughput in silico docking screen (using Autodock Vina 1.1.2), suramin has been identified as a potential inhibitor of hepsin, a transmembrane serine protease overexpressed in many cancers. ⁴² A subsequent fluorogenic assay with Boc-GIn-Arg-Arg-Amc substrate confirmed this (IC₅₀ = 0.66 μM) with an irreversible mechanism. At the half-maximal concentration, suramin significantly reduced the migration of Caco-2 cells stably transfected with a plasmid containing the HPN gene, both with basal expression rates and with hepsin overexpression.

Since hepsin activates Factor VII and thus the coagulation cascade, it could contribute to the hypercoagulability state of colorectal cancer patients with elevated levels of hepsin. To test the hypothesis, plasma was incubated from 20 healthy subjects. Suramin modified all key parameters toward normalization, achieving reductions in endogenous thrombin potential and velocity in reaching peak while causing an increase in the lag time of the thrombin generation phase and the time to reach the peak.

In zebrafish larvae, 0.66 μM suramin reduced the invasiveness of xenotransplanted hepsin-overexpressing Caco-2 cells almost to the levels of wild-type Caco-2 cells.—Suramin has shown promise in many cancer models (especially treatment-resistant prostate cancer) ⁴³ but activity against hepsin had not yet been reported, and could ameliorate thrombophilia in colorectal cancer patients.

TOPICAL SERTRALINE PROTECTS AGAINST RADIATION DAMAGE

WO/2023/049262, Composition and Method for Prevention and Treatment of Cutaneous Radiation Injury (Inventors: Hardy RL, Brigell M; applicant: Rythera Therapeutics, Inc., Miami Lakes, Florida, USA; published: March 30, 2023).

This invention concerns a method for ameliorating or preventing cutaneous radiation injury, resulting from environmental exposure to radiation for industrial, military, or medical radioactive sources, by topical application of functional inhibitors of acid sphingomyelinase. Among these are selective serotonin reuptake inhibitors (sertraline being preferred) ⁴⁴ and tricyclic antidepressants (amitriptyline), ⁴⁵ in addition to other drug classes. Acid sphingomyelinase is central to the response of cells to stress and the induction of cell death. It catalyzes the hydrolysis of sphingomyelin to ceramide, especially in response to radiation, which then induces apoptosis. ^46,47

A randomized double-blind study was conducted in 14 subjects aged 18 years or older who recently underwent breast cancer surgery and who were scheduled to undergo a standard course of radiation therapy of 1.8 to 2.0 Gy per session for between 25 and 30 sessions over a 5- to 6-week period administered as 5 consecutive daily treatments per week. Patients were randomized 2:1 to receive RAD-100 (sertraline topical cream 4.00% w/w) or vehicle cream twice a day. Radiation dermatitis did not develop earlier than day 26 except in a few subjects.

The results showed p-values favorable to the treated group throughout the treatment period and into the postradiation period. Although radiation-induced dermatitis worsened in the placebo group during the 7-day postradiation period, the mean score stabilized in the treated group and healing appeared to be faster. All p-values were in favor of the treated group, although none approached statistical significance.—Notably, the osteoporosis drug zoledronate, a potent inhibitor of farnesyl pyrophosphate synthase (a key branch point in the isoprenoid biosynthetic pathway), also has radioprotective properties (see WO/2014/162123 and WO/2014/162124), as does the tyrosine kinase inhibitor, dasatinib (WO/2016/131972); these documents were discussed in earlier issues of this journal).