Abstract 2819: Identification and characterization of a novel smoothened antagonist for the treatment of cancer with deregulated hedgehog signaling

Bender, Mark H.; Hipskind, Philip A.; Capen, Andrew; Cockman, Michael D.; Credille, Kelly M.; Gao, Hong; Bastian, Jolie A.; Clay, Julia M.; Lobb, Karen L.; Sall, Daniel J.; Thompson, Michelle L.; Wilson, Takako; Wishart, Graham N.; Patel, Bharvin K.R.

doi:10.1158/1538-7445.am2011-2819

Cited by 44 publications

(25 citation statements)

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“…Mutation of D473 6.55 into histidine has been identified as a cause of chemoresistance for GDC-0449, while LY2940680 has been reported to be unaffected by this mutation 24 . To investigate the role of D473 6.55 in the binding of different ligands, we performed 3 H-cyclopamine competition binding assays on a D473 6.55 A mutant, as well as an E518 7.38 A mutant that could impact the conformation of D473 6.55 .…”

Section: Resultsmentioning

confidence: 99%

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Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs

et al. 2014

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The Smoothened receptor (SMO) mediates signal transduction in the hedgehog pathway, which is implicated in normal development and carcinogenesis. SMO antagonists can suppress the growth of some tumors; however, mutations at SMO have been found to abolish their anti-tumor effects, a phenomenon known as chemoresistance. Here we report three crystal structures of human SMO bound to the antagonists SANT1 and Anta XV, and the agonist, SAG1.5, at 2.6–2.8Å resolution. The long and narrow cavity in the transmembrane domain of SMO harbors multiple ligand binding sites, where SANT1 binds at a deeper site as compared with other ligands. Distinct interactions at D4736.55 elucidated the structural basis for the differential effects of chemoresistance mutations on SMO antagonists. The agonist SAG1.5 induces a conformational rearrangement of the binding pocket residues, which could contribute to SMO activation. Collectively, these studies reveal the structural basis for the modulation of SMO by small molecules.

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Section: Resultsmentioning

confidence: 99%

“…LY2940680, for example, has been reported to bind the D473 6.55 H mutant that provides chemoresistance to the approved cancer drug GDC-0449 24 . This biological phenomenon accords nicely with our structural analysis, which shows that LY2940680 forms weak interactions with D473 6.55 .…”

Section: Discussionmentioning

confidence: 99%

Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs

et al. 2014

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“…Taladegib (LY2940680) is a SMO inhibitor that binds to the extracellular end of the transmembranehelix bundle of SMO and inhibits SMO mutants that are vismodegib-resistant [9,59] . There are eight active studies on taladegib.…”

Section: Smo Inhibitorsmentioning

confidence: 99%

Biochemical pathways and targeted therapies in basal cell carcinoma: A systematic review

2016

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Basal cell carcinoma (BCC) is the most common type of human malignancy. It is a slow-growing skin cancer with little ability to metastasize, but it is aggressive and can cause local tissue destruction. Descriptions of Basal Cell Nevus Syndrome (BCNS), characterized by a predisposition to the formation of BCC and other neoplasms, and identification of the genetic defect in this syndrome, has led to significant advancement in our understanding of the pathogenesis of BCC. Unregulated expression of target genes in the sonic Hedgehog (SHH) signaling pathway plays a prominent role in the pathogenesis of BCC. An understanding of the signaling components has allowed for the development of pharmacologic agents that inhibit the SHH pathway. The first inhibitor of the SHH pathway approved by the Food and Drug Administration (FDA) for the treatment of BCC is vismodegib. In this review, we will discuss the biochemical pathways involved in BCC as targets of novel pharmacologic therapies.

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“…Asp-473, a residue that when mutated to histidine confers resistance to the anti-cancer agent Vismodegib (GDC-0449) (55,56), lines the drug-binding pocket but interacts differently with different antagonists and does not confer universal drug resistance (43). Asp-473 does not directly contact LY2940680, for example, and the D473H substitution does not affect the activity of LY2940680 (57). The variable susceptibility of individual drugs to resistance mutations suggests that second generation drugs or combination therapies may prolong the time to development of resistance.…”

Section: Smoothened: 7tm Regionmentioning

confidence: 99%

Smoothened Goes Molecular: New Pieces in the Hedgehog Signaling Puzzle

McCabe¹,

Leahy

2015

Journal of Biological Chemistry

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A general aim of studies of signal transduction is to identify mediators of specific signals, order them into pathways, and understand the nature of interactions between individual components and how these interactions alter pathway behavior. Despite years of intensive study and its central importance to animal development and human health, our understanding of the Hedgehog (Hh) signaling pathway remains riddled with gaps, question marks, assumptions, and poorly understood connections. In particular, understanding how interactions between Hh and Patched (Ptc), a 12-pass integral membrane protein, lead to modulation of the function of Smoothened (Smo), a 7-pass integral membrane protein, has defied standard biochemical characterization. Recent structural and biochemical characterizations of Smoothened domains have begun to unlock this riddle, however, and lay the groundwork for improved cancer therapies. Members of the Hedgehog (Hh)3 family of secreted signaling proteins are present in most metazoans and owe their name to the effects that loss of Hh function has on Drosophila embryos, which lose their normal segmented pattern and develop a uniform coat of bristles reminiscent of the coats of hedgehogs (1). As presaged by this phenotype, Hh proteins mediate essential tissue patterning events during many stages of animal development (2), and abnormal Hh function is associated with birth defects and cancer (3). Hh proteins are also involved in tissue maintenance and wound repair in adult animals (4). Hh proteins achieve their patterning effects by functioning as classical morphogens (5). That is, Hh proteins form gradients of decreasing concentration from sites of secretion and induce concentration-dependent differentiation of distinct cell types (6, 7). As befits a morphogen, Hh expression, release, diffusion, and signal reception are tightly regulated by multiple factors (8).Classical and modern genetic techniques have identified several cell-surface proteins and glycans involved in receiving or modifying Hh signals (9). The core components of this process, conserved in all organisms known to have active Hh signaling, are Patched (Ptc) and Smoothened (Smo) (Fig. 1) (10 -13). Ptc functions upstream of Smo and has been genetically and biochemically defined as a primary component of the Hh receptor (14,15). Ptc is a 12-pass integral membrane protein with distant homology to bacterial resistance-nodulation-cell division (RND) transporters (16,17). Transmembrane helices 2-6 of Ptc are also homologous to sterol-sensing domains, which are found in diverse integral membrane proteins and regulate activity in response to levels of free cellular sterols (18). Smo is a member of the Frizzled family (class F) of G-protein coupled receptors (GPCRs) (19), and contains an N-terminal, ϳ14-kDa extracellular cysteine-rich domain (CRD) connected via a linker to 7 membrane-spanning helices (7TM) and an extended (ϳ200 amino acids, human; ϳ450 amino acids, Drosophila) C-terminal tail.Hh signaling responses are modulated by additional ce...

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Abstract 2819: Identification and characterization of a novel smoothened antagonist for the treatment of cancer with deregulated hedgehog signaling

Cited by 44 publications

References 0 publications

Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs

Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs

Biochemical pathways and targeted therapies in basal cell carcinoma: A systematic review

Smoothened Goes Molecular: New Pieces in the Hedgehog Signaling Puzzle

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