Intermittent dosing of the transforming growth factor beta receptor 1 inhibitor, BMS-986260, mitigates class-based cardiovascular toxicity in dogs but not rats.
TGFβ
TGFβ receptor inhibitor
cardiovascular toxicity
dog
rat
valvulopathy
Journal
Journal of applied toxicology : JAT
ISSN: 1099-1263
Titre abrégé: J Appl Toxicol
Pays: England
ID NLM: 8109495
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
25
11
2019
revised:
07
01
2020
accepted:
26
01
2020
pubmed:
16
2
2020
medline:
21
10
2021
entrez:
16
2
2020
Statut:
ppublish
Résumé
Small-molecule inhibitors of transforming growth factor beta receptor 1 (TGFβRI) have a history of significant class-based toxicities (eg, cardiac valvulopathy) in preclinical species that have limited their development as new medicines. Nevertheless, some TGFβRI inhibitors have entered into clinical trials using intermittent-dosing schedules and exposure limits in an attempt to avoid these toxicities. This report describes the toxicity profile of the small-molecule TGFβRI inhibitor, BMS-986260, in rats and dogs. Daily oral dosing for 10 days resulted in valvulopathy and/or aortic pathology at systemic exposures that would have been targeted clinically, preventing further development with this dosing schedule. These toxicities were not observed in either species in 1-month studies using the same doses on an intermittent-dosing schedule of 3 days on and 4 days off (QDx3 once weekly). Subsequently, 3-month studies were conducted (QDx3 once weekly), and while there were no cardiovascular findings in dogs, valvulopathy and mortality occurred early in rats. The only difference compared to the 1-month study was that the rats in the 3-month study were 2 weeks younger at the start of dosing. Therefore, a follow-up 1-month study was conducted to evaluate whether the age of rats influences sensitivity to target-mediated toxicity. Using the same dosing schedule and similar doses as in the 3-month study, there was no difference in the toxicity of BMS-986260 in young (8 weeks) or adult (8 months) rats. In summary, an intermittent-dosing schedule mitigated target-based cardiovascular toxicity in dogs but did not prevent valvulopathy in rats, and thus the development of BMS-986260 was terminated.
Substances chimiques
Enzyme Inhibitors
0
Transforming Growth Factor beta
0
Receptor, Transforming Growth Factor-beta Type I
EC 2.7.11.30
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
931-946Informations de copyright
© 2020 John Wiley & Sons, Ltd.
Références
Aikawa, E., Whittaker, P., Farber, M., Mendelson, K., Padera, R. F., Aikawa, M., & Schoen, F. J. (2006). Human semilunar cardiac valve remodeling by activated cells from fetus to adult: implications for postnatal adaptation, pathology, and tissue engineering. Circulation, 113(10), 1344-1352. https://doi.org/10.1161/CIRCULATIONAHA.105.591768
Akhurst, R. J., & Hata, A. (2012). Targeting the TGFβ signalling pathway in disease. Nature Reviews Drug Discovery, 11(10), 790-811. https://doi.org/10.1038/nrd3810
Anderton, M. J., Mellor, H. R., Bell, A., Sadler, C., Pass, M., Powell, S., … Heier, A. (2011). Induction of heart valve lesions by small-molecule ALK5 inhibitors. Toxicologic Pathology, 39(6), 916-924. https://doi.org/10.1177/0192623311416259
Chanut, F., Kimbrough, C., Hailey, R., Berridge, B., Hughes-Earle, A., Davies, R., … York, M. (2013). Spontaneous cardiomyopathy in young Sprague-Dawley rats: evaluation of biological and environmental variability. Toxicologic Pathology, 41(8), 1126-1136. https://doi.org/10.1177/0192623313478692
Chen, M.-L., Pittet, M. J., Gorelik, L., Flavell, R. A., Weissleder, R., Von Boehmer, H., & Khazaie, K. (2005). Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-β signals in vivo. Proceedings of the National Academy of Sciences, 102(2), 419-424.
Charles River Laboratories Datasheet: CD IGS rats (Crl: CD [SD]). (2011). Retrieved from https://www.criver.com/sites/default/files/resources/CDIGSRatModelInformationSheet.pdf
Derynck, R., & Miyazono, K. (2008). 2 TGF-β and the TGF-β Family. Cold Spring Harbor Monograph Archive, 50, 29-43.
Elangbam, C. S., Job, L. E., Zadrozny, L. M., Barton, J. C., Yoon, L. W., Gates, L. D., & Slocum, N. (2008). 5-hydroxytryptamine (5HT)-induced valvulopathy: compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats. Experimental and Toxicologic Pathology, 60(4-5), 253-262. https://doi.org/10.1016/j.etp.2008.03.005
Frazier, K. (2008). Investigative toxicology: The state of the art. Workshop Summary: Paper presented at the Emerging Safety Science.
Frazier, K., Thomas, R., Scicchitano, M., Mirabile, R., Boyce, R., Zimmerman, D., … Gellibert, F. (2007). Inhibition of ALK5 signaling induces physeal dysplasia in rats. Toxicologic Pathology, 35(2), 284-295. https://doi.org/10.1080/01926230701198469
Gueorguieva, I., Cleverly, A. L., Stauber, A., Pillay, N. S., Rodon, J. A., Miles, C. P., … Lahn, M. M. (2014). Defining a therapeutic window for the novel TGF-β inhibitor LY2157299 monohydrate based on a pharmacokinetic/pharmacodynamic model. British Journal of Clinical Pharmacology, 77(5), 796-807. https://doi.org/10.1111/bcp.12256
Herbertz, S., Sawyer, J. S., Stauber, A. J., Gueorguieva, I., Driscoll, K. E., Estrem, S. T., … Benhadji, K. A. (2015). Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Design, Development and Therapy, 9, 4479-4499.
Hinton, R. B. Jr., Lincoln, J., Deutsch, G. H., Osinska, H., Manning, P. B., Benson, D. W., & Yutzey, K. E. (2006). Extracellular matrix remodeling and organization in developing and diseased aortic valves. Circulation Research, 98(11), 1431-1438.
Judge, D. P., & Dietz, H. C. (2005). Marfan's syndrome. Lancet, 366(9501), 1965-1976. https://doi.org/10.1016/S0140-6736(05)67789-6
Kasparov, S., & Paton, J. F. (1997). Changes in baroreceptor vagal reflex performance in the developing rat. Pflügers Archiv, 434(4), 438-444.
Katsuda, S.-i., Waki, H., Yamasaki, M., Nagayama, T., O-Ishi, H., Katahira, K., & Shimizu, T. (2002). Postnatal changes in the rheological properties of the aorta in Sprague-Dawley rats. Experimental Animals, 51(1), 83-93. https://doi.org/10.1538/expanim.51.83
Kubiczkova, L., Sedlarikova, L., Hajek, R., & Sevcikova, S. (2012). TGF-β-an excellent servant but a bad master. Journal of Translational Medicine, 10, 1-24.
Kulkarni, A. B., Huh, C. G., Becker, D., Geiser, A., Lyght, M., Flanders, K. C., … Karlsson, S. (1993). Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proceedings of the National Academy of Sciences, 90(2), 770-774. https://doi.org/10.1073/pnas.90.2.770
Li, W., Li, Q., Jiao, Y., Qin, L., Ali, R., Zhou, J., … Dietz, H. C. (2014). Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis. The Journal of Clinical Investigation, 124(2), 755-767. https://doi.org/10.1172/JCI69942
Liu, R.-M., & Desai, L. P. (2015). Reciprocal regulation of TGF-β and reactive oxygen species: a perverse cycle for fibrosis. Redox Biology, 6, 565-577. https://doi.org/10.1016/j.redox.2015.09.009
Loeys, B. L., Chen, J., Neptune, E. R., Judge, D. P., Podowski, M., Holm, T., … Sharifi, N. (2005). A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nature Genetics, 37(3), 275-281.
Loeys, B. L., Schwarze, U., Holm, T., Callewaert, B. L., Thomas, G. H., Pannu, H., … Dietz, H. C. (2006). Aneurysm syndromes caused by mutations in the TGF-beta receptor. New England Journal of Medicine, 355(8), 788-798. https://doi.org/10.1056/NEJMoa055695
Nacif, M., & Shaker, O. (2014). Targeting Transforming Growth Factor-[beta](TGF-[beta]) in Cancer and Non-Neoplastic Diseases. Journal of Cancer Therapy, 5(7), 735-747.
Ng, C. M., Cheng, A., Myers, L. A., Martinez-Murillo, F., Jie, C., Bedja, D., … Judge, D. P. (2004). TGF-β-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. The Journal of Clinical Investigation, 114(11), 1586-1592. https://doi.org/10.1172/JCI22715
Park, B. V., Freeman, Z. T., Ghasemzadeh, A., Chattergoon, M. A., Rutebemberwa, A., Steigner, J., … Lee, S.-J. (2016). TGFβ1-mediated SMAD3 enhances PD-1 expression on antigen-specific T cells in cancer. Cancer Discovery, 6(12), 1366-1381. https://doi.org/10.1158/2159-8290.CD-15-1347
Rodon Ahnert, J., Baselga, J., Calvo, E., Seoane, J., Brana, I., Sicart, E., … Pillay, S. (2011). First human dose (FHD) study of the oral transforming growth factor-beta receptor I kinase inhibitor LY2157299 in patients with treatment-refractory malignant glioma. Journal of Clinical Oncology, 29(15_suppl), 3011-3011.
Shen, J., Li, J., Wang, B., Jin, H., Wang, M., Zhang, Y., … Chen, D. (2013). Deletion of the transforming growth factor β receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice. Arthritis and Rheumatism, 65(12), 3107-3119. https://doi.org/10.1002/art.38122
Stauber, A., Credille, K., Truex, L., Ehlhardt, W., & Young, J. (2014). Nonclinical safety evaluation of a transforming growth factor β receptor I kinase inhibitor in Fischer 344 rats and beagle dogs. Journal of Clinical Toxicology, 4(3), 1-10.
Takeda, N., Hara, H., Fujiwara, T., Kanaya, T., Maemura, S., & Komuro, I. (2018). TGF-beta Signaling-Related Genes and Thoracic Aortic Aneurysms and Dissections. International Journal of Molecular Sciences, 19(7), 1-19. https://doi.org/10.3390/ijms19072125
Velaparthi, U., Darne, C., Warrier, J., Liu, P., Rahaman, H., Fargnoli, J., … Borzilleri, R. M. (In press). Discovery and evaluation of BMS-986260, a potent, selective and orally bioavailable TGFβR1 inhibitor as an immuno-oncology agent. ACS Medicinal Chemistry Letters..
Walshe, T. E., Saint-Geniez, M., Maharaj, A. S., Sekiyama, E., Maldonado, A. E., & D'Amore, P. A. (2009). TGF-β is required for vascular barrier function, endothelial survival and homeostasis of the adult microvasculature. PLoS ONE, 4(4), 1-16. https://doi.org/10.1371/journal.pone.0005149
Yang, L., Pang, Y., & Moses, H. L. (2010). TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends in Immunology, 31(6), 220-227. https://doi.org/10.1016/j.it.2010.04.002
Yang, X., Chen, L., Xu, X., Li, C., Huang, C., & Deng, C.-X. (2001). TGF-β/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. The Journal of Cell Biology, 153(1), 35-46. https://doi.org/10.1083/jcb.153.1.35
Yingling, J. M., McMillen, W. T., Yan, L., Huang, H., Sawyer, J. S., Graff, J., … Driscoll, K. E. (2018). Preclinical assessment of galunisertib (LY2157299 monohydrate), a first-in-class transforming growth factor-beta receptor type I inhibitor. Oncotarget, 9(6), 6659-6677. https://doi.org/10.18632/oncotarget.23795