Synthesis and structure–activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of Dorsomorphin: The discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe
ABSTRACT A structure-activity relationship of the 3- and 6-positions of the pyrazolo[1,5-a]pyrimidine scaffold of the known BMP inhibitors dorsomorphin, 1, LDN-193189, 2, and DMH1, 3, led to the identification of a potent and selective compound for ALK2 versus ALK3. The potency contributions of several 3-position substituents were evaluated with subtle structural changes leading to significant changes in potency. From these studies, a novel 5-quinoline molecule was identified and designated an MLPCN probe molecule, ML347, which shows >300-fold selectivity for ALK2 and presents the community with a selective molecular probe for further biological evaluation.
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ABSTRACT: Fibrodysplasia ossificans progressiva (FOP) is the most disabling disorder of skeletal metamorphosis in humans and leads to the formation of a second skeleton of heterotopic bone. Presently, there is no effective treatment. In this review, the authors discuss heterozygous activating mutations in Activin receptor A, type I/ Activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor that are the genetic cause of FOP and reveal a promising pharmacologic target in the BMP signaling pathway. Despite these germline mutations, episodic disease activation is induced by soft tissue injury and resultant inflammatory triggers that are dependent on responding progenitor cells and a tissue microenvironment that supports heterotopic ossification. Here we review opportunities and challenges for the development of effective therapeutics for FOP. There are many potential approaches that may eventually be used to harness FOP. The long-term treatment of FOP is likely to involve not one, but several concomitant approaches that acknowledge molecular mechanisms involved in the induction and progression of the disease.08/2013; 1(8):637-649. DOI:10.1517/21678707.2013.825208
Article: A bone to pick with zebrafish.[Show abstract] [Hide abstract]
ABSTRACT: The development of high-throughput sequencing and genome-wide association studies allows us to deduce the genetic factors underlying diseases much more rapidly than possible through classical genetics, but a true understanding of the molecular mechanisms of these diseases still relies on integrated approaches including in vitro and in vivo model systems. One such model that is particularly suitable for studying bone diseases is the zebrafish (Danio rerio), a small fresh-water teleost that is highly amenable to genetic manipulation and in vivo imaging. Zebrafish physiology and genome organization are in many aspects similar to those of humans, and the skeleton and mineralizing tissues are no exception. In this review, we highlight some of the contributions that have been made through the study of mutant zebrafish that feature bone and/or mineralization disorders homologous to human diseases, including osteogenesis imperfecta, fibrodysplasia ossificans progressiva and generalized arterial calcification of infancy. The genomic and phenotypic similarities between the zebrafish and human cases are illustrated. We show that, despite some systemic physiological differences between mammals and teleosts, and a relative lack of a history as a model for bone research, the zebrafish represents a useful complement to mouse and tissue culture systems in the investigation of genetic bone disorders.11/2013; 2:445. DOI:10.1038/bonekey.2013.179
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ABSTRACT: Pharmacologic agents to enhance liver regeneration after injury would have wide therapeutic application. Based on previous work suggesting inhibition of Bone Morphogenetic Protein (BMP) signaling stimulates liver regeneration, we tested known and novel BMP-inhibitors for their ability to accelerate regeneration in a partial hepatectomy (PH) model. Compounds produced based on the 3,6-disubstituted pyrazolo[1,5-a] pyrimidine core of the BMP antagonist dorsomorphin (DM) were evaluated for their ability to inhibit BMP signaling and enhance liver regeneration. Antagonists of the BMP receptor activin receptor-like kinase 3 (Alk3), including LDN-193189 (LDN), DMH2 (VU0364849), and the novel compound VU0465350 (VU5350), blocked SMAD phosphorylation in vitro and in vivo and enhanced liver regeneration after PH. In contrast, an antagonist of the BMP receptor Alk2, VU0469381 (1LWY or ML347), did not affect liver regeneration. LDN did not affect liver synthetic or metabolic function. Mechanistically, LDN increased serum IL-6 levels and STAT3 phosphorylation in the liver, and modulated other factors known to be important for liver regeneration, including Socs3, and p53. These findings suggest that inhibition of Alk3 may be part of a therapeutic strategy for treating human liver disease.Journal of Pharmacology and Experimental Therapeutics 09/2014; DOI:10.1124/jpet.114.216903