Crenolanib Besylate

Researchers invented a new reporting technique to monitor activity of CaMKII while screening the effects of nearly 5,000 FDA approved drugs on human cells that expressed the enzyme. The screen identified five previously unknown CaMKII inhibitors; ruxolitinib, which is used to treat cancers of the blood and bone marrow, along with skin conditions like atopic dermatitis and vitiligo, was the most effective. Ruxolitinib, a drug that is already approved by the U.S. Food and Drug Administration (FDA) for treating certain cancers and skin conditions, is effective at inhibiting CaMKII, a protein kinase linked to cardiac arrhythmias. In a new study published June 21, 2023, in Science Translational Medicine, researchers from Johns Hopkins University and the University of Chicago invented a new reporting technique to monitor activity of CaMKII while screening the effects of nearly 5,000 FDA approved drugs on human cells that expressed the enzyme. The screen identified five previously unknown CaMKII inhibitors; ruxolitinib, which is used to treat cancers of the blood and bone marrow, along with skin conditions like atopic dermatitis and vitiligo, was the most effective. CaMKII, or Calcium and calmodulin-dependent protein kinase II, is critical to cardiomyocytes, the muscle cells of the heart, where it maintains the balance of calcium. Activation of CaMKII helps facilitate rapid changes in heart activity, such as initiating a fight-or-flight response in the body. Overactivation can lead to impaired heart function and cell death, which can in turn lead to poor heart health outcomes like arrhythmia. CaMKII is perhaps best known, however, for its role in the brain, where it is believed to play key roles in learning and memory. This has slowed the development of CaMKII inhibitors to treat arrythmia, for fear they could impact cognitive function. "Finding an FDA approved drug means that millions of people have been taking CaMKII inhibitors, and in the case of ruxolitinib, there are no reported major problems with the brain," said Mark Anderson, MD, PhD, a senior author of the paper and Dean of the Biological Sciences Division and Pritzker School of Medicine, Executive Vice President for Medical Affairs, and Paul and Allene Russell Professor at the University of Chicago. "That should give pharma and biotech companies confidence that they could carry out development of a CaMKII inhibitor program, because the biggest obstacle seems to be surmountable." The research began in Anderson's lab at Johns Hopkins University, where he previously served as the William Osler Professor and Director of the Department of Medicine. Oscar Reyes Gaido, the study's first author and an MD-PhD student in the lab, developed a new tool to measure activity of CaMKII in living cells. He started with a protein called green fluorescent protein (GFP), originally derived from jellyfish, that emits green light. He then engineered the GFP tag to detect CaMKII activation, making a new reporter called CaMKAR (CaMKII Activity Reporter). When this reporter was inserted into human heart cells, it helpfully glowed bright green whenever CaMKII became active, allowing researchers to monitor enzyme activity. "This biosensor will be very useful for studying how CaMKII activity changes in both healthy and pathological contexts. Existing methods can measure CaMKII activity, but they lack the versatility and resolution to track in real time and with high sensitivity," Reyes Gaido said. "This has been a real obstacle for studying enzyme biology in general, so this gives the field an important new tool." Using this tool, the researchers conducted a drug repurposing screen to test the effects of 4,475 approved compounds on cultured human cardiomyocytes. This identified five previously unknown CaMKII inhibitors: ruxolitinib, baricitinib, silmitasertib, crenolanib, and abemaciclib. Of the five, ruxolitinib was the most effective at inhibiting CaMKII activity in cell and mouse models of CaMKII-driven arrhythmias. A 10-minute application of the drug was enough to prevent catecholaminergic polymorphic ventricular tachycardia (CPVT), a congenital source of pediatric cardiac arrest, and rescue atrial fibrillation, the most common clinical arrhythmia. Crucially, the mice treated with ruxolitinib did not show any adverse cognitive effects when they were tested with memory and learning tasks. Anderson said that new drugs based on ruxolitinib could be used in several ways to treat heart conditions. One would be what he called the "pill in a pocket" scenario. In the early stages of atrial fibrillation, people could take the medication occasionally as symptoms arise. Patients with CPVT are often resistant to standard treatments, and a ruxolitinib-based treatment could provide another option. Finally, there is evidence that inhibiting CaMKII during a heart attack can prevent heart muscle from dying, so emergency responders could potentially administer such a drug as part of standard practice. "There's been a long search for fundamental pathways that could be targets for therapeutics in arrhythmias," Anderson said. "This could be a finding that will translate relatively rapidly into people now since it's already been proven to be safe in humans."

SAN DIEGO and TORONTO, May 02, 2022 (GLOBE NEWSWIRE) -- Aptose Biosciences Inc. (“Aptose” or the “Company”) (NASDAQ: APTO, TSX: APS), a clinical-stage precision oncology company developing highly differentiated oral kinase inhibitors to treat hematologic malignancies, today highlighted recent publications of preclinical data for luxeptinib (CG-806) in three peer-reviewed scientific journals. Luxeptinib, Aptose’s oral, dual lymphoid and myeloid kinome inhibitor, is an investigational drug currently in two Phase 1 a/b trials: one in patients with relapsed or refractory B cell malignancies, and separately in patients with relapsed or refractory acute myeloid leukemias (AML) or high-risk myelodysplastic syndromes (MDS). Recent Journal Articles: Luxeptinib disables NLRP3 inflammasome-mediated IL-1β release and pathways required for secretion of inflammatory cytokines IL-6 and TNFα Biochemical Pharmacology (2022)195 114861 Luxeptinib is an orally bioavailable kinase inhibitor with potency against select kinases including BTK. Aberrant activation of inflammasomes act as drivers of pathological complications observed during autoimmune and inflammatory disorders, metabolic syndromes, and cancer; and inhibiting the inflammasome-induced activation of pro-inflammatory cytokines has shown beneficial effects in human disease models. BTK and certain other kinases serve as an integral components or influence functions of the NLRP3 inflammasome complex. The aim of this study was to determine if luxeptinib interferes with the release of IL-1β, IL-6 and TNFα from THP-1 monocytes and bone marrow-derived macrophages following endotoxin exposure and priming of the NLRP3 inflammasome. Key findings: Luxeptinib inhibits NLRP3 inflammasome function in THP-1 monocytes and bone marrow-derived macrophages. Mechanistically, luxeptinib prevents the release of cleaved IL-1β from THP-1 cells by inhibiting the ability of the NLRP3 inflammasome to proteolytically cleave caspase-1 to its active form. Luxeptinib does not impede the assembly of the NLRP3-ASC complex but does potently inhibit three kinases phosphorylated in response to endotoxin. Phosphorylation and nuclear translocation of transcription factor NF-κBp65 was inhibited by luxeptinib. Luxeptinib also inhibits the release of TNFα and IL-6 in response to activation of the TLR pathway without affecting the TLR/IRAK/MyD88 proteins. These studies provide novel insights into the mechanisms by which luxeptinib interferes with the NLRP3 inflammasome and endotoxin-induced inflammatory signaling pathways, along with its protective effects against inflammation-induced toxicity in murine models. The ability of luxeptinib to inhibit inflammatory pathways at concentrations which are well-tolerated in patients makes it a potential clinical candidate for the treatment of inflammatory diseases and inflammation-associated resistance in cancer. Dual BTK/SYK inhibition with CG-806 (luxeptinib) disrupts B-cell receptor and Bcl-2 signaling networks in mantle cell lymphoma Cell Death & Disease -Nature (2022)13:246. Small molecules BTK inhibitors like ibrutinib are approved for the treatment of mantle cell lymphoma, or MCL, a rare subtype of non-Hodgkin’s lymphoma (NHL). Nevertheless, median duration of response is less than two years, and MCL patients who develop therapeutic resistance have poor outcomes. Resistance to BTK inhibitors is not clearly understood and a number of alternative mechanisms have been implicated. Luxeptinib, previously known as CG-806, inhibits LYN, SYK, and BTK activation, potently inhibiting both wildtype and C481S mutant BTK, and is expected to have activity in settings where resistance to BTK inhibitors is driven by these mutations. In a Phase 1 trial in patient with chronic lymphocytic leukemia (CLL) and NHL, treatment with luxeptinib resulted in decreased phosphorylation of SYK and BTK in the circulating malignant cells within eight hours of administration. This current pre-clinical study investigates mechanism and efficacy of luxeptinib in MCL. Key findings: Luxeptinib induced apoptosis in ibrutinib-resistant MCL cell lines, and in primary MCL cells luxeptinib downmodulated anti-apoptotic proteins Mcl-1 and Bcl-xL and reversed stromal cell survival effects. Luxeptinib, but not ibrutinib, blocked SYK and BTK signaling and inhibited ERK phosphorylation in MCL cell lines and primary MCL cells. Dual suppression of BTK/SYK activation with luxeptinib demonstrated efficacy in a PDX MCL model, where efficacy was accompanied by downmodulation of Bcl-2 family proteins and NFκB. Luxeptinib induced metabolic reprogramming toward a glycolytic shift in MCL cells, accompanied by mitochondrial depolarization and induction of mitophagy that eliminates dysfunctional mitochondria and leads to cell death. Luxeptinib Inhibits BTK/SYK/ERK signaling and is a potentially promising new therapy in MCL and NHL. Luxeptinib (CG-806) targets FLT3 and clusters of kinases operative in acute myeloid leukemia Molecular Cancer Therapeutics (2022),Mol. Cancer Ther. molcanther.0832.2021. AML cells survive via dysregulation of multiple pathways, including FLT3 mutations that occur in approximately 30% of AML patients and are associated with increased risk of relapse and poor survival. Luxeptinib, currently in a Phase 1a/b clinical trial for the treatment of AML, potently inhibits both FLT3 and many of the kinases that participate in rescue pathways that contribute to relapsed and refractory disease. In this study, researchers investigated the range of kinases it inhibits, its antiproliferative landscape ex vivo with AML patient samples, and its in vivo efficacy in xenograft models. Key findings: Luxeptinib, an oral non-covalent kinase inhibitor, potently suppresses wild type and mutant forms of FLT3 and select clusters of kinases that can participate in rescue pathways. Oral luxeptinib demonstrated strong antitumor activity in preclinical in vivo AML xenograft models but no myelosuppression or evidence of tissue damage in acute toxicology studies. Importantly, luxeptinib does not inhibit the TEC, EGFR, or ERBB2 kinases that can be associated with cardiac, skin and bleeding adverse events. Ex vivo profiling of luxeptinib against 186 AML fresh patient samples demonstrated greater potency relative to other FLT3 inhibitors, including cases with mutations in FLT3, IDH1/2, ASXL1, NPM1, SRSF2, TP53 or RAS. A combination of venetoclax and luxeptinib enhanced cell killing of the majority of AML samples relative to either drug alone. Luxeptinib retained activity against FLT3 mutants that render cells resistant to quizartinib, gilteritinib, and crenolanib FLT3 inhibitors. “These publications contribute to the wealth of preclinical data demonstrating luxeptinib’ s unique activity as a lymphoid and myeloid kinome inhibitor, and now as an inflammation kinome inhibitor, and support its continued clinical development in several therapeutic areas,” said William G. Rice, Ph.D., Chairman, President, and Chief Executive Officer. “Luxeptinib is a clinical-stage compound, currently in Phase 1 a/b studies in AML and B-cell malignancies. We look forward to reporting on our progress in the upcoming months.” About Aptose Aptose Biosciences is a clinical-stage biotechnology company committed to developing personalized therapies addressing unmet medical needs in oncology, with an initial focus on hematology. The Company's small molecule cancer therapeutics pipeline includes products designed to provide single agent efficacy and to enhance the efficacy of other anti-cancer therapies and regimens without overlapping toxicities. The Company has two clinical-stage investigational products under development for hematologic malignancies: HM43239, an oral, myeloid kinome inhibitor in an international Phase 1/2 trial in patients with relapsed or refractory acute myeloid leukemia (AML); and luxeptinib, an oral, dual lymphoid and myeloid kinome inhibitor in a Phase 1 a/b trial in patients with relapsed or refractory B-cell malignancies who have failed or are intolerant to standard therapies, and in a separate Phase 1 a/b trial in patients with relapsed or refractory AML or high risk myelodysplastic syndrome (MDS). For more information, please visit .