Distinct Mechanistic Signatures of the JAK2 Inhibitors Revealed by BioMAP Phenotypic Profiling Published in PLOS ONE
Distinct Mechanistic Signatures of the JAK2 Inhibitors Ruxolitinib, Fedratinib, Momelotinib, and Pacritinib Revealed by BioMAP Phenotypic Profiling Published in PLOS ONE
NEWS PROVIDED BY:
Eurofins Discovery
November 04, 2019, 10:30ET
As of August 2019, two small molecule kinase inhibitors targeting JAK2 (ruxolitinib and fedratinib) have FDA approval for treatment of myelofibrosis—a type of bone marrow cancer in which fibrous scar tissue forms in the bone marrow, causing the primary site of red blood cell production to move to the spleen and liver, with subsequent organ enlargement and complications. An additional two JAK2 inhibitors (momelotinib and pacritinib) have progressed to advanced clinical development. Although all four kinase inhibitors have shown proven clinical benefit or potential for benefit in myelofibrosis, diverse patient outcomes observed with these inhibitors – including adverse effects – suggest distinct off-target or secondary activities.
A collaborative effort developed between scientists at CTI Biopharma of Seattle, Washington and Eurofins Discovery Phenotypic Services begins to shed light on these diverse impacts, by comparing translational biomarker profiles for the four JAK2 inhibitors using the systems biology approach of the BioMAP® Phenotypic Profiling Platform.
Their recent findings published in PLOS ONE revealed that the drugs have multiple common activities in human primary cell-based disease systems modeling B and T cell activation responses, consistent with their shared JAK2 target and relevance for myelofibrosis. However, distinct biomarker profiles for each drug also reveal distinct secondary pharmacology for the inhibitors, even at doses equivalent to clinical exposures, not just, as is sometimes the case, at higher doses.
“The current study was performed to evaluate the biological effects of these agents on normal human cells derived from a variety of tissues. Each was shown to have distinct profiles with major differences in biological selectivity that may suggest explanations for their differential toxicity profiles and additional directions for clinical trials in diseases other than myeloproliferative disorders,” says study lead Jack Singer, MD, Clinical Professor of Medicine, Washington State University, Floyd Elson College of Medicine.
“Pre-clinical evaluation of test agents for discriminating activities is challenging but critical to assess superiority over competitive benchmarks. The BioMAP Diversity PLUS® Panel provided an unbiased and translationally relevant platform to evaluate the selectivity and secondary pharmacology of multiple JAK2 inhibitors,” says Alison O’Mahony PhD, VP Translational Biology at Eurofins Discovery.
These newly published findings are found in the article, “Comparative phenotypic profiling of the JAK2 inhibitors ruxolitinib, fedratinib, momelotinib, and pacritinib reveals distinct mechanistic signatures.” Results in the article demonstrate the utility and value of BioMAP phenotypic profiling for autoimmune, oncology and other applications—not only for efficacy and safety in early discovery, but throughout pipeline development, including head-to-head testing and into the clinic.
Reference: Singer JW, Al-Fayoumi S, Taylor J, Velichko S, O’Mahony A. Comparative phenotypic profiling of the JAK2 inhibitors ruxolitinib, fedratinib, momelotinib, and pacritinib reveals distinct mechanistic signatures. PLOS ONE. 2019;14(9):e0222944.
NEWS PROVIDED BY:
Eurofins Discovery
November 04, 2019, 10:30ET
As of August 2019, two small molecule kinase inhibitors targeting JAK2 (ruxolitinib and fedratinib) have FDA approval for treatment of myelofibrosis—a type of bone marrow cancer in which fibrous scar tissue forms in the bone marrow, causing the primary site of red blood cell production to move to the spleen and liver, with subsequent organ enlargement and complications. An additional two JAK2 inhibitors (momelotinib and pacritinib) have progressed to advanced clinical development. Although all four kinase inhibitors have shown proven clinical benefit or potential for benefit in myelofibrosis, diverse patient outcomes observed with these inhibitors – including adverse effects – suggest distinct off-target or secondary activities.
A collaborative effort developed between scientists at CTI Biopharma of Seattle, Washington and Eurofins Discovery Phenotypic Services begins to shed light on these diverse impacts, by comparing translational biomarker profiles for the four JAK2 inhibitors using the systems biology approach of the BioMAP® Phenotypic Profiling Platform.
Their recent findings published in PLOS ONE revealed that the drugs have multiple common activities in human primary cell-based disease systems modeling B and T cell activation responses, consistent with their shared JAK2 target and relevance for myelofibrosis. However, distinct biomarker profiles for each drug also reveal distinct secondary pharmacology for the inhibitors, even at doses equivalent to clinical exposures, not just, as is sometimes the case, at higher doses.
“The current study was performed to evaluate the biological effects of these agents on normal human cells derived from a variety of tissues. Each was shown to have distinct profiles with major differences in biological selectivity that may suggest explanations for their differential toxicity profiles and additional directions for clinical trials in diseases other than myeloproliferative disorders,” says study lead Jack Singer, MD, Clinical Professor of Medicine, Washington State University, Floyd Elson College of Medicine.
“Pre-clinical evaluation of test agents for discriminating activities is challenging but critical to assess superiority over competitive benchmarks. The BioMAP Diversity PLUS® Panel provided an unbiased and translationally relevant platform to evaluate the selectivity and secondary pharmacology of multiple JAK2 inhibitors,” says Alison O’Mahony PhD, VP Translational Biology at Eurofins Discovery.
These newly published findings are found in the article, “Comparative phenotypic profiling of the JAK2 inhibitors ruxolitinib, fedratinib, momelotinib, and pacritinib reveals distinct mechanistic signatures.” Results in the article demonstrate the utility and value of BioMAP phenotypic profiling for autoimmune, oncology and other applications—not only for efficacy and safety in early discovery, but throughout pipeline development, including head-to-head testing and into the clinic.
Reference: Singer JW, Al-Fayoumi S, Taylor J, Velichko S, O’Mahony A. Comparative phenotypic profiling of the JAK2 inhibitors ruxolitinib, fedratinib, momelotinib, and pacritinib reveals distinct mechanistic signatures. PLOS ONE. 2019;14(9):e0222944.
About BioMAP® Phenotypic Profiling
BioMAP Phenotypic Screening and Profiling Services provide an unbiased, target-agnostic and data-driven approach to understanding compound or combination therapy impact on in vitro human disease models and translational biomarkers. Validated with clinically approved drugs and known test agents, the BioMAP platform is powered by human primary cell-based disease systems, a Reference Database of over 4,500 compounds, advanced data analytics, and expert interpretation to provide clients with actionable insights. Email phenotypicsupport@eurofins.com.
About Eurofins Discovery
Eurofins Discovery, a business operating under the Eurofins BioPharma Services division, has supported Drug Discovery research for over 40 years. Eurofins is recognized as the industry leader for providing drug discovery researchers the largest and most diverse portfolio of standard and custom in vitro safety & pharmacology assays and panels for drug screening and profiling. In addition to in vitro safety pharmacology strengths, we also offer a broad portfolio of over 3500 drug discovery services and 1800 products. These include in vitro assays, cell-based phenotypic assays, safety pharmacology and efficacy, ADME toxicology, medicinal chemistry design, synthetic chemistry, and custom proteins and assay development capabilities. We support a variety of drug discovery targets such as GPCRs, Kinases, Ion Channels, Nuclear Hormone Receptors, and other proteins & enzymes. The Eurofins Discovery capabilities, expertise, knowledge and skillsets enable the company to provide clients the benefit of being able to work with a single outsourcing provider (CRO) for all their drug discovery programs.
About CTI BioPharma Corp.
CTI BioPharma Corp. is a biopharmaceutical company focused on the acquisition, development and commercialization of novel targeted therapies for blood-related cancers that offer a unique benefit to patients and their healthcare providers. In particular, CTI BioPharma is focused on evaluating pacritinib for the treatment of adult patients with myelofibrosis. CTI BioPharma is headquartered in Seattle, Washington.
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