Small-Molecule Ligands of Methyl-Lysine Binding Proteins

Herold, J. Martin; Wigle, Tim J.; Norris, Jacqueline L.; Lam, Robert; Korboukh, Victoria K.; Gao, Canzhu; Ingerman, Lindsey A.; Kireev, Dmitri; Senisterra, Guillermo; Vedadi, Masoud; Tripathy, Ashutosh; Brown, Peter J.; Arrowsmith, C.H.; Jin, Jian; Janzen, William P.; Frye, Stephen V.

doi:10.1021/jm200045v

Cited by 117 publications

(108 citation statements)

References 42 publications

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“…The conformationally rigid piperidino-pyrrolidine Kme mimic in UNC669 results in a ligand with fivefold greater affinity for L3MBTL1 than the H4K20me1 peptide-a presumed endogenous binding partner. UNC669 demonstrated moderate to high selectivity as a ligand for L3MBTL1 versus a small panel of other Kme binders with the next highest affinity being for L3MBTL3 (Herold et al, 2011b). A subsequent structure-activity relationship study of the UNC669 template revealed that pyrrolidine is an optimal size and shape for binding in the aromatic cage of L3MBTL1 that recognizes Kme and that an increase in ring size to piperidine was not tolerated (Herold et al, 2012).…”

Section: Selective Inhibitors Of Bromodomains and Methyl-lysine Readersmentioning

confidence: 99%

“…All active compounds from this screen contained a mono-or dialkylamine that presumably satisfies the mono-and dimethyllysine histone peptide preference of the MBT domains (Kireev et al, 2010). Subsequently, Herold et al (2011b) described the structure-and pharmacophore-based design of UNC669 (Fig. 4) that demonstrates a 5 mM dissociation constant (Kd) versus L3MBTL1 (Herold et al, 2011b).…”

Section: Selective Inhibitors Of Bromodomains and Methyl-lysine Readersmentioning

confidence: 99%

“…Subsequently, Herold et al (2011b) described the structure-and pharmacophore-based design of UNC669 (Fig. 4) that demonstrates a 5 mM dissociation constant (Kd) versus L3MBTL1 (Herold et al, 2011b). The conformationally rigid piperidino-pyrrolidine Kme mimic in UNC669 results in a ligand with fivefold greater affinity for L3MBTL1 than the H4K20me1 peptide-a presumed endogenous binding partner.…”

Section: Selective Inhibitors Of Bromodomains and Methyl-lysine Readersmentioning

confidence: 99%

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Writing and Rewriting the Epigenetic Code of Cancer Cells: From Engineered Proteins to Small Molecules

Blancafort¹,

Jin²,

Frye³

2012

Mol Pharmacol

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The epigenomic era has revealed a well-connected network of molecular processes that shape the chromatin landscape. These processes comprise abnormal methylomes, transcriptosomes, genome-wide histone post-transcriptional modifications patterns, histone variants, and noncoding RNAs. The mapping of these processes in large scale by chromatin immunoprecipitation sequencing and other methodologies in both cancer and normal cells reveals novel therapeutic opportunities for anticancer intervention. The goal of this minireview is to summarize pharmacological strategies to modify the epigenetic landscape of cancer cells. These approaches include the use of novel small molecule inhibitors of epigenetic processes specifically deregulated in cancer cells and the design of engineered proteins able to stably reprogram the epigenetic code in cancer cells in a way that is similar to normal cells.

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Section: Selective Inhibitors Of Bromodomains and Methyl-lysine Readersmentioning

confidence: 99%

Section: Selective Inhibitors Of Bromodomains and Methyl-lysine Readersmentioning

confidence: 99%

Section: Selective Inhibitors Of Bromodomains and Methyl-lysine Readersmentioning

confidence: 99%

See 1 more Smart Citation

Writing and Rewriting the Epigenetic Code of Cancer Cells: From Engineered Proteins to Small Molecules

Blancafort¹,

Jin²,

Frye³

2012

Mol Pharmacol

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“…11 The first example of this was pyrrolidine 17, as it represents a common motif of methyltransferase inhibitors that effectively binds to the lysinepeptide site.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2

Sweis

Wang

Algire

et al. 2015

ACS Med. Chem. Lett.

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A lack of useful small molecule tools has precluded thorough interrogation of the biological function of SMYD2, a lysine methyltransferase with known tumorsuppressor substrates. Systematic exploration of the structure−activity relationships of a previously known benzoxazinone compound led to the synthesis of A-893, a potent and selective SMYD2 inhibitor (IC 50 : 2.8 nM). A cocrystal structure reveals the origin of enhanced potency, and effective suppression of p53K370 methylation is observed in a lung carcinoma (A549) cell line. KEYWORDS: Epigenetics, SMYD2, H3K36, p53, methyltransferase, lysine SET and MYND domain-containing protein 2 (SMYD2) is a lysine methyltransferase that is highly expressed in esophageal squamous cell carcinoma and pediatric acute lymphoblastic leukemia.1,2 Elevated expression in both of these cancers correlates with a poor prognosis. Its function as a methyltransferase has been reported to span a variety of substrates including histone H3 (K36 3 and K4 4 ), retinoblastoma tumor suppressor (Rb) (K860), 5 and tumor suppressor p53 (K370). 6,7 It is through these processes that SMYD2 is believed to play a role in the network of post-translational modifications that regulates tumor growth. In particular, SMYD2 may serve as a putative oncogene by its methylation of lysine 370 of p53, which is repressive to p53 function.Despite the potential role of SMYD2 methylation in epigenetic regulation of the aforementioned cancers, no small molecule inhibitors of this enzyme were known until the disclosure of AZ505 (1) a few years ago (Figure 1). 8 This benzoxazinone was identified from a high-throughput screen (HTS) and shown via a cocrystal structure to bind to the lysine pocket of SMYD2. The potency of 1 toward SMYD2 was disclosed to be moderate (IC 50 : 120 nM) despite being quite selective (>700-fold) over six other methyltransferases. More recently, an additional SMYD2 inhibitor representing a new chemotype was published as a probe of the Structural Genomics Consortium (Figure 1). 9 LLY-507 (2) exhibited much improved potency (IC 50 < 15 nM) and inhibited p53K370 methylation in cells.As compound 1 represented the only known inhibitor of SMYD2 until recently, we pursued an avenue of investigation that systematically interrogated all binding elements of this molecule in order to inspire development of a more potent inhibitor.

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“…Compound 1 , which was prepared as a putative methyllysine binding domain inhibitor,23 was identified as a promising candidate for further optimization against KDM2A. However, attempts to significantly improve potency by functionalizing at the indole NH position and varying the aromatic substituent on the indole C‐2 position were unsuccessful.…”

mentioning

confidence: 99%

Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7

et al. 2017

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Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell‐permeable inhibitors or suitable tool compounds for these enzymes. We describe the discovery of a new class of inhibitor that is highly potent towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore the chemical space and accelerate the investigation of key structure–activity relationships, leading to the development of a small molecule with around 75‐fold selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar concentrations.

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Small-Molecule Ligands of Methyl-Lysine Binding Proteins

Cited by 117 publications

References 42 publications

Writing and Rewriting the Epigenetic Code of Cancer Cells: From Engineered Proteins to Small Molecules

Writing and Rewriting the Epigenetic Code of Cancer Cells: From Engineered Proteins to Small Molecules

Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2

Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7

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