Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function ...correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole-based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC50 = 0.002 μM, cellular EC50 = 0.032 μM) and selective inhibitor of EZH2. This compound demonstrates robust antitumor effects in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is currently in Phase I clinical trials. Additionally, we disclose the co-crystal structure of our inhibitor series bound to the human PRC2 complex.
A central feature of the lipid raft concept is the formation of cholesterol-rich lipid domains. The introduction of relatively rigid cholesterol molecules into fluid liquid-disordered (L
d) ...phospholipid bilayers can produce liquid-ordered (L
o) mixtures in which the rigidity of cholesterol causes partial ordering of the flexible hydrocarbon acyl chains of the phospholipids. Several lines of evidence support this concept, but direct structural information about L
o membranes is lacking. Here we present the structure of L
o membranes formed from cholesterol and dioleoylphosphatidylcholine (DOPC). Specific deuteration of the DOPC acyl-chain methyl groups and neutron diffraction measurements reveal an extraordinary disorder of the acyl chains of neat L
d DOPC bilayers. The disorder is so great that >20% of the methyl groups are in intimate contact with water in the bilayer interface. The ordering of the DOPC acyl chains by cholesterol leads to retraction of the methyl groups away from the interface. Molecular dynamics simulations based on experimental systems reveal asymmetric transbilayer distributions of the methyl groups associated with each bilayer leaflet.
In recent years, inhibition of the interaction between the bromodomain and extra-terminal domain (BET) family of chromatin adaptors and acetyl-lysine residues on chromatin has emerged as a promising ...approach to regulate the expression of important disease-relevant genes, including MYC, BCL-2, and NF-κB. Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610).
This paper describes the successful implementation of a stereocontrolled strategy for the total chemical synthesis of the pyrrolidine-based alkaloid (−)-kaitocephalin. This scalable synthetic route ...profits from the strategic utilization of substrate-controlled manipulations for the iterative installation of the requisite stereogenic centers. The key transformations include a diastereoselective modified Claisen condensation, a chemo- and diastereoselective reduction of a β-keto ester, and the substrate-directed hydrogenation of a dehydroamino ester derivative. During the course of our investigations, an interesting stereoconvergent cyclization reaction was discovered for the efficient assembly of the kaitocephalin 2,2,5-trisubstituted pyrrolidine core.
The synthetic strategy utilized to prepare clinical supplies of CRTH2 antagonist MK-1029 is described. Specifically, the approach communicated is predicated on the intervention of five distinct ...catalytic methods, using three separate metals and an enzyme, to enable successful construction of this complex active pharmaceutical ingredient.
This paper describes ongoing progress toward the synthesis of the novel indole alkaloid actinophyllic acid via a synthetic strategy that allows for the installation of all C-atoms (highlighted in ...red) requisite for completion of a total synthesis.
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The discovery and optimization of a series of small molecule EZH2 inhibitors is described. Starting from dimethylpyridone HTS hit (2), a series of indole-based EZH2 inhibitors were ...identified. Biochemical potency and microsomal stability were optimized during these studies and afforded compound 22. This compound demonstrates nanomolar levels of biochemical potency (IC50=0.002μM), cellular potency (EC50=0.080μM), and afforded tumor regression when dosed (200 mpk SC BID) in an EZH2 dependent tumor xenograft model.
A method for the synthesis of N-functionalized C2-/C3-substituted indoles via Pd-catalyzed C–N bond coupling of halo-aryl enamines is described. The general strategy utilizes a variety of amines and ...β-keto esters which are elaborated into halo-aryl enamines as latent precursors to indoles. The preferred conditions comprising the RuPhos precatalyst and RuPhos in the presence of NaOMe in 1,4-dioxane tolerate a variety of substituents and are scalable for the construction of indoles in multigram quantities.
Leveraging the catalytic machinery of LSD1 (KDM1A), a series of covalent styrenylcyclopropane LSD1 inhibitors were identified. These inhibitors represent a new class of mechanism-based inhibitors ...that target and covalently label the FAD cofactor of LSD1. The series was rapidly progressed to potent biochemical and cellular LSD1 inhibitors with good physical properties. This effort resulted in the identification of
, a highly potent (<4 nM biochemical, 2 nM cell, and 1 nM GI
), and selective LSD1 inhibitor. In-depth kinetic profiling of
confirmed its covalent mechanism of action, validated the styrenylcyclopropane as an FAD-directed warhead, and demonstrated that the potency of this inhibitor is driven by improved non-covalent binding (
).
demonstrated robust cell-killing activity in a panel of AML cell lines and robust antitumor activity in a Kasumi-1 xenograft model of AML when dosed orally at 1.5 mg/kg once daily.
Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and ...inflammatory disease, respectively. Herein we report substituted benzobisoxazolo4,5-dazepines and benzotriazolo4,3-d1,4diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of microsomal stability yielded representatives that demonstrated dose- and time-dependent reduction of plasma IL-6 in mice.
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