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  • br Indirect GLI antagonists br Direct GLI

    2021-09-14


    Indirect GLI antagonists
    Direct GLI antagonists
    Concluding remarks Targeting GLI effectors represents a promising therapeutic strategy for cancer treatment. This is particularly relevant for certain tumors, such as MB, since, although classified into four distinct molecular groups (Hh- or Wnt-type and 3rd or 4th), common signals, such as placental growth factor (PIGF)/neuropilin axis, responsible of GLI1 upregulation, are shared by all subtypes and are important for tumor growth [107]. Transcription factors are generally considered as challenging targets in drug discovery for many different reasons, including the lack of deep serotonin receptors pockets that accommodate small molecules and the highly charged surface. Nevertheless, big pharmaceutical companies are currently running Phase I clinical trials with small molecules targeting transcription factors such as Notch (Bristol-Myers Squibb and Ely Lilly) and p53 (Roche and Sanofi) [108], although no drugs have been approved yet by the FDA. Beside these targets, cMYC, NF-κB, signal transducer and activator of transcription (STAT)3, STAT5, AP1, hypoxia-inducible factor (HIF1), and GLI1 are among the most promising transcription factors for the development of new anticancer drugs. GLI functions are finely tuned by a number of molecular interactions and postsynthetic modifications (i.e., GLI1 phosphorylation, gene copy number amplification, BRD4-driven epigenetic activation, deubiquitylation, deacetylation, or activation by aPKCι,/k or p70S6K or RAS/ERK) that, if dysregulated, are responsible for the resistance to anti-SMO drugs frequently observed in Hh-driven tumor initiation, progression and relapse 16, 26, 109. Interestingly, GLI-processing and activating post-translational events are pharmacologically targetable, even though by means of combination therapies. For this reason, the challenge in this field is the understanding of the molecular mechanisms that regulate GLI-mediated transcription. In this regard, the recently reported identification of the structural requirements of GLI1/DNA interaction, stands as a promising tool for discovering small molecules capable of inhibiting Hh pathway by directly targeting GLI [106]. The discovery of the natural compound, GlaB, able to impair Hh oncogenic activity by inhibiting GLI1/DNA interaction, provides a proof-of-principle for the therapeutic relevance of such an approach, focused on the unique downstream GLI1 transcriptional effector rather than on multiple upstream oncogenic deregulated signals. Since the GLI proteins share highly conserved sequence of their ZF domain, targeting GLI1/DNA interaction could also interfere with GLI3/DNA binding, counteracting the GLI3 repressor function and resulting in severe side effects. However, the use of Hh antagonists is thought in a context of aberrant Hh pathway activation, where GLI repressor forms are absent, so bypassing the possibility of nonspecific effects on negative regulatory activity of GLI factors. Therefore, drugs specifically designed to modulate GLI/DNA interaction would provide valuable insights for developing and optimizing GLI antagonists, which would promise a more effective treatment of Hh-dependent tumors.
    Acknowledgments
    Main Text Tissue damage response pathways commonly summon myofibroblasts, the principal scar-forming cells. Owing to their rapid proliferation and extracellular matrix-making abilities, myofibroblasts can produce new tissue in a short period of time. However, such speed comes at the expense of quality, as scar tissue can only partially, if at all, substitute for normal tissue functions. Injuries such as skin wounds can trigger limited fibrosis, guided by normal wound healing mechanisms. However, fibrosis can take a sinister turn in diseases with a prominent inflammatory component, which elicit long-lasting and aggressive myofibroblast activation. In such instances, the continuously expanding myofibroblast population competes with and, ultimately, outcompetes normal resident cells, leading to a precipitous and even life-threatening loss of organ function. Until recently, myofibroblasts were thought to maintain a stable differentiated state after scar formation. This idea largely shaped the direction of anti-scarring strategies aimed at either suppressing myofibroblast activation or selectively eliminating them from tissues. Recent studies on skin wound healing (Plikus et al., 2017) and lung fibrosis (El Agha et al., 2017) are shifting this paradigm by showing that myofibroblasts remain plastic and can naturally convert into other tissue-specific cell types.