tolimidone (MTX228) / Melior, Bukwang Pharma, Adhera Therap, Biodexa Pharma - LARVOL DELTA

Lyn attenuates cisplatin-induced acute kidney injury by inhibition of RIPK1-mediated apoptosis and necroptosis. (PubMed, Biochem Pharmacol) - "Conversely, both Lyn agonist MLR-1023 and RIPK1 inhibitor Necrostatin-1 (Nec-1) attenuated cisplatin-triggered kidney injury, tubular cell apoptosis and necroptosis. In conclusion, our study revealed that Lyn protects from cisplatin-induced nephrotoxicity by suppressing RIPK1-mediated apoptosis, necroptosis and inflammation. Thus, Lyn kinase may serve as a promising therapeutic target for CP-AKI."

Journal • Acute Kidney Injury • Nephrology • Oncology • Renal Disease • Solid Tumor • LYN • RIPK1

Treml4 Drives Microglial Activation via the Lyn/Syk/ERK Pathway in Sepsis-Associated Encephalopathy. (PubMed, Neurochem Res) - "Similarly, knockdown of Treml4 could inhibit LPS-induced BV-2 cell activation, and the Lyn agonist Tolimidone (CP-26154) could reverse this effect in vitro. Treml4-mediated inflammatory and oxidative stress injury is crucial in the development of sepsis encephalopathy, indicating the potential role of Treml4 as a target for preventing and treating SAE."

Journal • CNS Disorders • Infectious Disease • Inflammation • Septic Shock • IL1B • IL6 • LYN • SYK • TNFA

Tyrosine kinase LYN restricts the replication and virulence of influenza A virus by directly phosphorylating viral nucleoprotein. (PubMed, mBio) - "The LYN-specific agonist MLR-1023 exhibited promising protective efficacy against lethal IAV infection. Our findings discovered LYN and LYN-agonist as potential drug candidates targeting IAV NP, which will facilitate the development of host-directed antiviral therapies."

Journal • Infectious Disease • Influenza • Respiratory Diseases • LYN

Tussilagone inhibits MRGPRX2-mediated mast cell degranulation and suppresses pseudo-allergic reactions. (PubMed, Toxicol Appl Pharmacol) - "Mechanistically, Tus inhibited tolimidone-induced Lyn kinase activation and suppressed SP-and Tween 80-induced β-hexosaminidase release, exhibiting an inhibitory profile comparable to that of the Lyn/Btk antagonist bosutinib. Additionally, Tus attenuated the phosphorylation levels of MRGPRX2 downstream signal molecules, including Btk, PLCγ1, PKC, p38 MAPK, IκB-α and NF-κB (p65). In conclusion, Tus attenuates SP-and Tween 80-induced mast cell activation and pseudo-allergic reactions by targeting the Lyn/Btk/PLCγ1 and p38/NF-κB pathways, highlighting its therapeutic potential for pseudo-allergy."

Journal • Allergy • Immunology • Oncology • CCL2 • CXCL8 • LYN • TNFA

Berberine: a promising strategy to combat cetuximab-resistance in colorectal cancer. (PubMed, BMC Cancer) - "Adding KX2-391 (Src inhibitor) rather than BML-277 (Chk-2 inhibitor) with cetuximab resulted in more cell death and apoptosis. Conversely, activation of Src with MLR-1023 mitigated the inhibitory effect of berberine alone or in combination with cetuximab. Additionally, the activities of downstream kinases of Src such as mTOR, STAT3 and the production of ROS were inhibited greatly by berberine plus cetuximab. Taken together, we concluded that the synergistic effects of BBR and cetuximab may be mediated by decreasing the activities of Src/mTOR/STAT3 and the production of ROS, thus inducing greater extent of apoptosis in cancer cells."

Journal • Colorectal Cancer • Oncology • Solid Tumor • EGFR • STAT3

Pyrimidine derivatives as multifaceted antidiabetic agents: A comprehensive review of structure-activity relationships, mechanisms, and clinical potential. (PubMed, Eur J Med Chem) - "The mechanistic insights from molecular docking and QSAR studies explain their interaction with different antidiabetic targets and clinical relevance is attributed to anagliptin and tolimidone. New vogue patterns, such as AI-drug designing and conjugate development, are discussed for next-generation therapies. The review covers also the perspectives on challenges, opportunities, and comparative merits over other heterocyclic scaffolds, making these pyrimidine derivatives versatile leads in exploring antidiabetic aspects."

Journal • Review • Developmental Disorders • Diabetes • Metabolic Disorders

Taletrectinib promotes pyroptosis in colorectal carcinoma via SRC/AKT/mTOR axis inhibition. (PubMed, Sci Rep) - "Moreover, the effect of taletrectinib in promoting pyroptosis was reversed by treatment with the SRC agonist, tolimidone, both in vitro and in vivo. Overall, our findings suggest that taletrectinib suppresses tumor growth by inducing GSDME-mediated pyroptosis via the SRC/AKT/mTOR signaling pathway, indicating that taletrectinib shows potential as a promising therapeutic agent against CRC."

Journal • Colorectal Cancer • Oncology • Solid Tumor • ANXA5 • CASP3 • GSDME • NTRK

An Adaptive Design Study of MTX228 (clinicaltrials.gov) - P2 | N=24 | Recruiting | Sponsor: University of Alberta | Not yet recruiting ➔ Recruiting

Enrollment open • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus

An Adaptive Design Study of MTX228 (clinicaltrials.gov) - P2 | N=24 | Not yet recruiting | Sponsor: University of Alberta | Trial primary completion date: Oct 2024 ➔ Oct 2026

Trial primary completion date • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus

A novel small-molecule activator of Lyn kinase for the treatment of type 1 diabetes (EASD 2024) - "Altogether, our results indicate that MLR1023 simultaneously promotes β-cell mass expansion and reduces islet inflammation, thereby correcting two defects that underlie T1D. This greatly increases our interest in MLR1023 as a potential anti-T1D medication."

Diabetes • Metabolic Disorders • Obesity • Type 1 Diabetes Mellitus • LYN • PCNA

Loss of LYN is frequent in targeted-therapy resistant melanoma cells and favors metastatic properties. (PubMed, J Invest Dermatol) - No abstract available

Journal • Metastases • Melanoma • Oncology • Solid Tumor

Biodexa - An Adaptive Design Study of MTX228 (clinicaltrials.gov) - P2 | N=24 | Not yet recruiting | Sponsor: University of Alberta

New P2 trial • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus

Lyn attenuates sepsis-associated acute kidney injury by inhibition of phospho-STAT3 and apoptosis. (PubMed, Biochem Pharmacol) - "Moreover, Lyn agonist MLR-1023 pretreatment improved renal function, inhibited STAT3 phosphorylation and decreased cell apoptosis. Thus, Lyn appears to play a crucial role in orchestrating STAT3-mediated inflammation and cell apoptosis in SA-AKI. Hence, Lyn kinase may be a promising therapeutic target for SA-AKI."

Journal • Acute Kidney Injury • Infectious Disease • Inflammation • Nephrology • Pneumonia • Renal Disease • Septic Shock • LYN • STAT3

Phenotypic screening of low molecular weight compounds is rich ground for repurposed, on-target drugs. (PubMed, Front Pharmacol) - "The diverse therapeutic activities described for this compound by us, and others arise from the same pleiotropic lyn kinase activation molecular target. MLR-1023 serves as a proof-of-principle that potent, on target, low MWT drugs can be discovered by phenotypic screening."

Journal • LYN

MLR-1023 Treatment in Mice and Humans Induces a Thermogenic Program, and Menthol Potentiates the Effect. (PubMed, Pharmaceuticals (Basel)) - P2a | "A glucose-lowering medication that acts by a different mechanism than metformin, or other approved diabetes medications, can supplement monotherapies when patients fail to meet blood glucose goals. The TRPM8 agonist, menthol, potentiated the effect of MLR-1023 on the upregulation of genes for energy expenditure and insulin sensitivity in human adipocytes, and reduced fasting blood glucose in mice. The amplification of the thermogenic program by MLR-1023 and menthol in the absence of adrenergic activation will likely be well-tolerated, and bears investigation in a clinical trial."

Journal • Preclinical • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Melior Pharmaceuticals Receives IND Clearance from US FDA for COVID-19 Therapeutic (Financial Post) - "Melior Pharmaceuticals (Melior) announced that it has received clearance of its Investigational New Drug (IND) application for the clinical development of its novel, first-in-class lyn kinase activator, tolimidone, for the treatment of COVID-19....The planned Phase 2 study is intended to recruit 236 subjects who were recently diagnosed with COVID-19, have early symptoms, but are not hospitalized. Tolimidone will be taken as an orally administered pill once a day."

Cytokine storm • IND • Infectious Disease • Novel Coronavirus Disease

Melior Pharmaceuticals Awarded Grant for Advancing Pulmonary Therapeutic in COVID-19 Phase 2 Clinical Trial (Businesswire) - "Melior Pharmaceuticals (Melior) has been awarded a grant from the Commonwealth of Pennsylvania’s COVID-19 Vaccines, Treatments and Therapies (CV-VTT) Program....The planned study is intended to recruit 428 subjects who were recently diagnosed with COVID-19, have early symptoms, but are not hospitalized. Tolimidone is expected to significantly mitigate the number of COVID-19 subjects who develop respiratory distress and the severity of respiratory distress if that should occur. Tolimidone will be taken as an orally administered pill once a day."

Cytokine storm • Grant • New P2 trial • Infectious Disease • Novel Coronavirus Disease

High throughput in vivo phenotypic screening for drug repurposing: Discovery of MLR-1023 a novel insulin sensitizer and novel Lyn kinase activator with clinical proof of concept. (PubMed, Bioorg Med Chem) - "In this article Chris Lipinski, the medicinal chemist, describes the chemical origins at Pfizer of Tolimidone the starting point for the repurposed MLR-1023 (Ochman et al., 2012). Andrew Reaume, the biologist, describes his motivation to develop a high quality (i.e. in vivo model) phenotypic screening platform as an ideal drug repositioning platform."

Journal • Review

Quercetin as a Lyn kinase inhibitor inhibits IgE-mediated allergic conjunctivitis. (PubMed, Food Chem Toxicol) - "This study illustrated the use of quercetin for the treatment of allergic conjunctivitis, which might act through its ability to inhibit Lyn/PLCγ/IP3R-Ca, Lyn/ERK1/2, and Lyn/NF-κB signaling. The inhibition of Lyn likely represents a major mechanism by which quercetin dampens the inflammatory response in AC disease models."

Journal

A novel non-PPARgamma insulin sensitizer: MLR-1023 clinicalproof-of-concept in type 2 diabetes mellitus. (PubMed, J Diabetes Complications) - P2a; "MLR-1023 100-mg once-daily for 4 weeks was the most effective dose with significant reduction in PPG AUC following a MMTT. MLR-1023 was safe and well-tolerated in patients with type 2 diabetes. Clinical Trials Registration Number: NCT02317796."

Clinical • Journal

An Add-on Study of MLR-1023 in Adults With Uncontrolled Type 2 Diabetes on Metformin Therapy (clinicaltrials.gov) - P2; N=400; Active, not recruiting; Sponsor: Melior Pharmaceuticals; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed