Discovery of Compound A - a selective activator of the glucocorticoid receptor with anti-inflammatory and anti-cancer activity

Abstract

Glucocorticoids are among the most effective anti-inflammatory drugs, and are widely used for cancer therapy. Unfortunately, chronic treatment with glucocorticoids results in multiple side effects. Thus, there was an intensive search for selective glucocorticoid receptor (GR) activators (SEGRA), which retain therapeutic potential of glucocorticoids, but with fewer adverse effects. GR regulates gene expression by transactivation (TA), by binding as homodimer to gene promoters, or transrepression (TR), via diverse mechanisms including negative interaction between monomeric GR and other transcription factors. It is well accepted that metabolic and atrophogenic effects of glucocorticoids are mediated by GR TA. Here we summarized the results of extensive international collaboration that led to discovery and characterization of Compound A (CpdA), a unique SEGRA with a proven “dissociating” GR ligand profile, preventing GR dimerization and shifting GR activity towards TR both in vitro and in vivo. We outlined here the unusual story of compound's discovery, and presented a comprehensive overview of CpdA ligand properties, its anti-inflammatory effects in numerous animal models of inflammation and autoimmune diseases, as well as its anti-cancer effects. Finally, we presented mechanistic analysis of CpdA and glucocorticoid effects in skin, muscle, bone, and regulation of glucose and fat metabolism to explain decreased CpdA side effects compared to glucocorticoids. Overall, the results obtained by our and other laboratories underline translational potential of CpdA and its derivatives for treatment of inflammation, autoimmune diseases and cancer.

Phytosteroids beyond estrogens: Regulators of reproductive and endocrine function in natural products

“…Using bioassay guided fractionation, the active compound was eventually determined to be an unstable aziridine compound which was stabilized i n vivo through interactions with serum proteins (Louw et al, 1997). In addition, the investigators synthesized a more stable aziridine analog that they named “compound A” (4-[1-Chloro-2-(methylamino)ethyl]phenyl acetate hydrochloride (1:1)) (Figure 1; Lesovaya et al, 2015; Swart et al, 2003, 1993). …”

“…Compound A reduced the proliferation and induced apoptosis of prostate cancer cell lines DU145 and PC3 in vitro , in a GR-dependent manner (Yemelyanov et al, 2008). Additionally, compound A slowed growth of PC3 and Granta-519 xenografts in vivo (Lesovaya et al, 2015) making it a promising therapeutic lead based on a phytosteroid (Lesovaya et al, 2015). …”

“…Phytosteroids have diverse structures, sometimes very different from the endogenous steroid (Figure 1); yet they can act as agonists, antagonists, or frequently have mixed agonist/antagonist activity for steroid receptors (Lesovaya et al, 2015; Toh et al, 2012). In addition, some phytosteroids interact with multiple steroid receptors (Pihlajamaa et al, 2011) or interfere with steroid metabolizing enzymes (Blachley and Knochel, 1980), thus having complex effects on the endocrine and reproductive systems.…”

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“…Of these Compound A (CpdA) was the earliest to be identified and was first isolated from the Namibian shrub (Salsola tuberculatiformis). This non-steroidal compound when investigated was found to bind atypically to the GR in ligand binding essays but with high affinity, and was thought it may be using different coupling points in the Ligand binding domain of the GR or by inducing a unique conformation of the GR which is not yet understood [20][21][22][23][24].…”

“…In addition this compound is widely studied in in vitro and in vivo studies however the narrow therapeutic index of this compound alongside its structural malleability limits its use in the real world but does make it an effective platform to research the concept. For instance in an animal model of Multiple Sclerosis (MS), CpdA showed repression of myelin specific T-effector cells through downregulation of cell adhesion molecules but was noted to cause apoptosis in several cell lines including lymphocytes with weight loss a common side effect (24) . In addition in an inflammatory bowel disease study both CpdA and ZK216348 had wound healing properties by positively upregulating intestinal cell proliferation and migration.…”