Meeting report: the 2020 FSHD International Research Congress
Kyba M, Bloch RJ, Dumonceaux J, Harper SQ, van der Maarel SM, Sverdrup FM, Wagner KR, van Engelen B and Chen YW
Meeting report: the 2020 FSHD International Research Congress
Kyba M, Bloch RJ, Dumonceaux J, Harper SQ, van der Maarel SM, Sverdrup FM, Wagner KR, van Engelen B and Chen YW
Clinically Advanced p38 Inhibitors Suppress DUX4 Expression in Cellular and Animal Models of Facioscapulohumeral Muscular Dystrophy
Oliva J, Galasinski S, Richey A, Campbell AE, Meyers MJ, Modi N, Zhong JW, Tawil R, Tapscott SJ and Sverdrup FM
Clinically Advanced p38 Inhibitors Suppress DUX4 Expression in Cellular and Animal Models of Facioscapulohumeral Muscular Dystrophy
Oliva J, Galasinski S, Richey A, Campbell AE, Meyers MJ, Modi N, Zhong JW, Tawil R, Tapscott SJ and Sverdrup FM
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by misexpression of the double homeobox 4 (DUX4) developmental transcription factor in mature skeletal muscle, where it is responsible for muscle degeneration. Preventing expression of DUX4 mRNA is a disease-modifying therapeutic strategy with the potential to halt or reverse the course of disease. We previously reported that agonists of the -2 adrenergic receptor suppress expression by activating adenylate cyclase to increase cAMP levels. Efforts to further explore this signaling pathway led to the identification of p38 mitogen-activated protein kinase as a major regulator of expression. In vitro experiments demonstrate that clinically advanced p38 inhibitors suppress expression in FSHD type 1 and 2 myoblasts and differentiating myocytes in vitro with exquisite potency. Individual small interfering RNA-mediated knockdown of either p38 or p38 suppresses expression, demonstrating that each kinase isoform plays a distinct requisite role in activating Finally, p38 inhibitors effectively suppress expression in a mouse xenograft model of human FSHD gene regulation. These data support the repurposing of existing clinical p38 inhibitors as potential therapeutics for FSHD. The surprise finding that p38 and p38 isoforms each independently contribute to DUX4 expression offers a unique opportunity to explore the utility of p38 isoform-selective inhibitors to balance efficacy and safety in skeletal muscle. We propose p38 inhibition as a disease-modifying therapeutic strategy for FSHD. SIGNIFICANCE STATEMENT: Facioscapulohumeral muscular dystrophy (FSHD) currently has no treatment options. This work provides evidence that repurposing a clinically advanced p38 inhibitor may provide the first disease-modifying drug for FSHD by suppressing toxic DUX4 expression, the root cause of muscle degeneration in this disease.
BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells
Campbell AE, Oliva J, Yates MP, Zhong JW, Shadle SC, Snider L, Singh N, Tai S, Hiramuki Y, Tawil R, van der Maarel SM, Tapscott SJ and Sverdrup FM
BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells
Campbell AE, Oliva J, Yates MP, Zhong JW, Shadle SC, Snider L, Singh N, Tai S, Hiramuki Y, Tawil R, van der Maarel SM, Tapscott SJ and Sverdrup FM
Facioscapulohumeral dystrophy (FSHD) is a progressive muscle disease caused by mutations that lead to epigenetic derepression and inappropriate transcription of the double homeobox 4 (DUX4) gene in skeletal muscle. Drugs that enhance the repression of DUX4 and prevent its expression in skeletal muscle cells therefore represent candidate therapies for FSHD.
Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates
Faidallah HM, Panda SS, Serrano JC, Girgis AS, Khan KA, Alamry KA, Therathanakorn T, Meyers MJ, Sverdrup FM, Eickhoff CS, Getchell SG and Katritzky AR
Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates
Faidallah HM, Panda SS, Serrano JC, Girgis AS, Khan KA, Alamry KA, Therathanakorn T, Meyers MJ, Sverdrup FM, Eickhoff CS, Getchell SG and Katritzky AR
Click chemistry technique led to novel 1,2,3-triazole-quinine conjugates 8a-g, 10a-o, 11a-h and 13 utilizing benzotriazole-mediated synthetic approach with excellent yields. Some of the synthesized analogs (11a, 11d-h) exhibited antimalarial properties against Plasmodium falciparum strain 3D7 with potency higher than that of quinine (standard reference used) through in vitro standard procedure bio-assay. Statistically significant BMLR-QSAR model describes the bio-properties, validates the observed biological observations and identifies the most important parameters governing bio-activity.
Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents
Meyers MJ, Anderson EJ, McNitt SA, Krenning TM, Singh M, Xu J, Zeng W, Qin L, Xu W, Zhao S, Qin L, Eickhoff CS, Oliva J, Campbell MA, Arnett SD, Prinsen MJ, Griggs DW, Ruminski PG, Goldberg DE, Ding K, Liu X, Tu Z, Tortorella MD, Sverdrup FM and Chen X
Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents
Meyers MJ, Anderson EJ, McNitt SA, Krenning TM, Singh M, Xu J, Zeng W, Qin L, Xu W, Zhao S, Qin L, Eickhoff CS, Oliva J, Campbell MA, Arnett SD, Prinsen MJ, Griggs DW, Ruminski PG, Goldberg DE, Ding K, Liu X, Tu Z, Tortorella MD, Sverdrup FM and Chen X
Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined antimalarial datasets for drug-like aspartic protease inhibitors. This effort led to the identification of spiropiperidine hydantoins, bearing similarity to known inhibitors of the human aspartic protease β-secretase (BACE), as new leads for antimalarial drug discovery. Spiropiperidine hydantoins have a dynamic structure-activity relationship profile with positions identified as being tolerant of a variety of substitution patterns as well as a key piperidine N-benzyl phenol pharmacophore. Lead compounds 4e (CWHM-123) and 12k (CWHM-505) are potent antimalarials with IC50 values against Plasmodium falciparum 3D7 of 0.310 μM and 0.099 μM, respectively, and the former features equivalent potency on the chloroquine-resistant Dd2 strain. Remarkably, these compounds do not inhibit human aspartic proteases BACE, cathepsins D and E, or Plasmodium plasmepsins II and IV despite their similarity to known BACE inhibitors. Although the current leads suffer from poor metabolic stability, they do fit into a drug-like chemical property space and provide a new class of potent antimalarial agents for further study.