Abstract Although the treatment landscape of advanced urothelial cancer (UC) has changed dynamically over the last decade, metastatic UC still has amongst the worst 5-year recurrence rate of any cancer type, highlighting the need for new therapeutic options for these patients. Analogous to breast cancer, advanced UC is a heterogeneous disease, with luminal and basal subtypes. For luminal breast cancer, small molecule targeting of the lineage-defining transcription factor estrogen receptor (ER) is a demonstrated and effective therapeutic strategy. Two-thirds of advanced UC is classified as luminal, which is characterized by overexpression of the urothelial lineage-defining transcription factor PPARG. Thus, small molecule targeting of PPARG in luminal UC may serve as a therapeutic strategy analogous to ER in luminal breast cancer. While PPARG agonists have been well studied in the context of metabolic disease, PPARG inhibitors have received far less attention. Previously reported PPARG inhibitors display minimal phenotypic activity in pre-clinical UC models, calling into question the performance of these molecules, or alternatively, the role of PPARG as a survival lineage oncogene in UC. Leveraging reconstituted, multi-component PPARG biochemical systems, we first identified the limitations of previous tool compounds and then discovered a novel, covalent lead series with unique, context-dependent electrophilic properties. These efforts lead to the discovery of FX-909, a first-in-class covalent PPARG inverse agonist with powerful repressive conformational biasing activity. FX-909 is highly potent in cells (IC50=1 nM), demonstrates high specificity for PPARG (>2000-fold selective over PPARA/PPARD), and elicits robust in vitro growth inhibition in UC cell lines with activated PPARG signaling. Tumor regression was observed in UMUC9 (PPARG amplification) and HT1197 (RXRAS427F hotspot mutation) xenograft models of UC with oral dosing at 1 mg/kg. Predictable, on-target and reversible pharmacology was observed at FX-909 doses above 1 mg/kg, mimicking PPARG loss-of-function mutations with notable tissue remodeling in adipose tissue and the normal urothelium. These collective findings corroborate the role of PPARG as a key UC survival oncogene and suggest that FX-909 will be an effective therapy for patients with advanced UC harboring the luminal subtype. Citation Format: Robert Sims, Jennifer A. Mertz, Jonathan E. Wilson, James E. Audia, Kaylyn E. Williamson, Yong Li, Miljan Kuljanin, Will W. Motely, Byron DeLaBarre, Michaela Bowden, Jacob I. Stuckey. Discovery of FX-909, a first-in-class inverse agonist of the peroxisome proliferator-activated receptor gamma (PPARG) lineage transcription factor, to potentially treat patients with the luminal subtype of advanced urothelial cancer (UC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND08.

Therapeutic targeting of the estrogen receptor (ER) is a clinically validated approach for estrogen receptor positive breast cancer (ER+ BC), but sustained response is limited by acquired resistance. Targeting the transcriptional coactivators required for estrogen receptor activity represents an alternative approach that is not subject to the same limitations as targeting estrogen receptor itself. In this report we demonstrate that the acetyltransferase activity of coactivator paralogs CREBBP/EP300 represents a promising therapeutic target in ER+ BC. Using the potent and selective inhibitor CPI-1612, we show that CREBBP/EP300 acetyltransferase inhibition potently suppresses in vitro and in vivo growth of breast cancer cell line models and acts in a manner orthogonal to directly targeting ER. CREBBP/EP300 acetyltransferase inhibition suppresses ER-dependent transcription by targeting lineage-specific enhancers defined by the pioneer transcription factor FOXA1. These results validate CREBBP/EP300 acetyltransferase activity as a viable target for clinical development in ER+ breast cancer.

A focused SAR study was conducted on a series of N1-substituted pyrazolopyrimidinone PDE2 inhibitors to reveal compounds with excellent potency and selectivity. The series was derived from previously identified internal leads and designed to enhance steric interactions with key amino acids in the PDE2 binding pocket. Compound 26 was identified as a lead compound with excellent PDE2 selectivity and good physicochemical properties.

The histone acetyltransferases, CREB binding protein (CBP) and EP300, are master transcriptional co-regulators that have been implicated in numerous diseases, such as cancer, inflammatory disorders, and neurodegeneration. A novel, highly potent, orally bioavailable EP300/CBP histone acetyltransferase (HAT) inhibitor, CPI-1612 or 17, was developed from the lead compound 3. Replacement of the indole scaffold of 3 with the aminopyridine scaffold of 17 led to improvements in potency, solubility, and bioavailability. These characteristics resulted in a 20-fold lower efficacious dose for 17 relative to lead 3 in a JEKO-1 tumor mouse xenograft study.

EP300 and CBP (KAT3A/3B) are two highly homologous, multidomain, epigenetic coregulators that play central roles in transcription through the acetylation of lysine residues on histones and other proteins. Both enzymes have been implicated in human diseases, especially cancer. From a high‐throughput screen of 191 000 compounds searching for EP300/CBP histone acetyltransferase (HAT) inhibitors, 18 compounds were characterized by a suite of biochemical enzymatic assays and biophysical methods, including X‐ray crystallography and native mass spectrometry. This work resulted in the discovery of three distinct mechanistic classes of EP300/CBP HAT inhibitors, including two classes not previously described. The profiles of an example of each class of inhibitor are described in detail. A subsequent medicinal chemistry effort led to the development of a novel class of orally bioavailable AcCoA‐competitive EP300/CBP HAT inhibitors with in vivo activity. We believe that this work will prove to be a useful guide for other groups interested in the development of HAT inhibitors.

A new synthesis of isoindolinones was discovered during a screening campaign aimed at the development of novel methods for the synthesis of pyridone-EZH2 inhibitor analogues. The reaction proceeds via an intramolecular [4+2] cycloaddition of a pyridone with a tethered propiolamide moiety followed by extrusion of isocyanic acid. The discovery, optimization, and scope of the methodology are described. (C) 2019 Elsevier Ltd. All rights reserved.

A novel series of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists are described. The series was designed to address the suboptimal PK (pharmacokinetic) and off-target profile of a class of N-aryl-benzo-[1,4]-oxazepine-4-carboxamides, represented by 1, that were identified from a high-throughput screen of the Merck compound collection for GPR142 agonists. This work led to the discovery of 3-phenoxy-benzo-[1,2,4]-triazolo-[1,4]-oxazepine 47, a potent GPR142 agonist with an off-target and PK profile suitable for in vivo studies. This compound and a related analogue 40 were shown to be active in mouse oral glucose tolerance tests (OGTTs). Furthermore, a GPR142 knock-out mouse OGTT study with compound 40 provides evidence that its glucose-lowering effect is mediated by GPR142.

Using the collective body of known (CETP) inhibitors as inspiration for design, a structurally novel series of tetrahydroquinoxaline CETP inhibitors were discovered. An exemplar from this series, compound 5, displayed potent in vitro CETP inhibition and was efficacious in a transgenic cynomologus-CETP mouse HDL PD (pharmacodynamic) assay. However, an undesirable metabolic profile and chemical instability hampered further development of the series. A three-dimensional structure of tetrahydroquinoxaline inhibitor 6 was proposed from (1)H NMR structural studies, and this model was then used in silico for the design of a new class of compounds based upon an indoline scaffold. This work resulted in the discovery of compound 7, which displayed potent in vitro CETP inhibition, a favorable PK-PD profile relative to tetrahydroquinoxaline 5, and dose-dependent efficacy in the transgenic cynomologus-CETP mouse HDL PD assay.

The incorporation of a methyl group into a small molecule can have a profound impact on its biological activity, pharmacokinetic profile, and physical properties. As part of an ongoing effort to develop novel methods for methylation of small molecule drug candidates, a three-component coupling of aryliodides, O-benzoylamines, and methylboronic acid that proceeds via a Catellani-type mechanism has been developed. The methodology allows for the ortho-amination/ipso-methylation of aryl- and heteroaryliodides with a wide variety of cyclic O-benzoylamines including pyrrolidines, piperidines, piperazines, morpholines, azepines, diazepines, and azocanes in a single step. A preliminary result for an ortho-methylation/ipso-olefination Catellani-type three component-coupling reaction is also described. (C) 2016 Elsevier Ltd. All rights reserved.

In 2003, Tomita reported an intriguing P(n-Bu)3-catalyzed diastereoselective cyclization of certain yne-diones to form bicyclic furanones that bear two new stereocenters (Figure 1).[1] He proposed that conjugate addition of the phosphine to the alkyne is followed by tautomerization, which furnishes zwitterionic enolate A. Next, an intramolecular aldol reaction provides B, and then a second conjugate addition generates bicycle C (the conversion of A to C via a concerted cycloaddition may also be considered). Tautomerization and then elimination of the phosphine affords the bicyclic furanone. Tomita’s investigation focused on symmetrical substrates (i.e., R1 = –C≡CR), although he did report reactions of two unsymmetrical yne-diones, which cyclized in relatively modest yield (41–50%).

A method for the diastereoselective synthesis of tetrahydroquinolines via a palladium-catalyzed Suzuki terminated Heck reaction is described. The reaction provides access to tetrahydroquinolines containing both quaternary and tertiary stereocenters. Ligand effects, a rationale for the high level of diastereoselectivity, and a mechanistic hypothesis are discussed.

Complementary palladium-catalyzed methods for direct arylation of oxazole with high regioselectivity (>100:1) at both C-5 and C-2 have been developed for a wide range of aryl and heteroaryl bromides, chlorides, iodides, and triflates. C-5 arylation is preferred in polar solvents with phosphines 5 or 6, whereas C-2 arylation is preferred by nonpolar solvents and phosphine 3. This represents the first general method for C-5 selective arylation of oxazole and should see broad applicability in the synthesis of biologically active molecules. Additionally, potential mechanisms for these two competing arylation processes are proposed on the basis of mechanistic observations.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

In 2003, Tomita reported an intriguing P(n-Bu)3-catalyzed diastereoselective cyclization of certain yne-diones to form bicyclic furanones that bear two new stereocenters (Figure 1).[1] He proposed that conjugate addition of the phosphine to the alkyne is followed by tautomerization, which furnishes zwitterionic enolate A. Next, an intramolecular aldol reaction provides B, and then a second conjugate addition generates bicycle C (the conversion of A to C via a concerted cycloaddition may also be considered). Tautomerization and then elimination of the phosphine affords the bicyclic furanone. Tomita’s investigation focused on symmetrical substrates (i.e., R1 = –C≡CR), although he did report reactions of two unsymmetrical yne-diones, which cyclized in relatively modest yield (41–50%). Figure 1 Phosphine-catalyzed reaction of yne-diones to form bicyclic furanones (for the sake of simplicity, the steps are drawn as irreversible). This study by Tomita provides an excellent illustration of how the use of a nucleophilic catalyst can open the door to new modes of reactivity.[2] Surprisingly, to the best of our knowledge there have been no subsequent investigations that further develop this interesting reaction manifold (i.e., conjugate-addition/cross-tautomerization to generate a dipolar intermediate such as A). In this report, we exploit this reactivity to achieve phosphine-catalyzed diastereoselective transformations of acyclic precursors into highly functionalized diquinanes that bear multiple (three or four) contiguous stereocenters [Eq. (1)].[3] (1) Not only are diquinanes (including bicyclo[3.3.0]octan-2-ones) subunits of a wide array of bioactive compounds, but they are also versatile intermediates in organic synthesis.[4,5] We envisioned that a phosphine-catalyzed method for the generation of such structures might be viable (Krische has also developed a powerful phosphine-catalyzed approach to the synthesis of diquinanes[6]), if a zwitterion derived from 1 (analogous to A in Figure 1) could be induced to undergo an intramolecular Michael, rather than an aldol, reaction. Unfortunately, when subjected to the conditions developed by Tomita, compound 1 was not transformed into the target diquinane in significant yield [<10% yield; Eq. (2)]. (2) Upon investigating a variety of reaction parameters (e.g., catalyst, temperature, solvent, and concentration), we determined that the desired reaction manifold can be achieved through the appropriate choice of solvent and concentration. Thus, by conducting the cyclization in CH2Cl2/EtOAc (9/1) under more dilute conditions, we can efficiently generate the target diquinane, which bears three new contiguous stereocenters and an E double bond, as a single diastereomer [89% yield; Eq. (2)].[7] This phosphine-catalyzed reaction can be applied to the stereoselective synthesis of an array of diquinanes (Table 1; in each case, a single diastereomer is produced).[8] For example, the alkyne subunit can include an aromatic, alkenyl, or alkyl group (see R in Table 1); the ability to achieve cyclizations of alkyl-substituted compounds (entries 4, 7, 8, and 11) is noteworthy, since β-alkyl-substituted ynones are susceptible to phosphine-catalyzed isomerization to conjugated dienones.[9] The linker between the ynone and the enoate can bear substituents (e.g., entries 5–9) or include an aromatic ring (entries 10 and 11). Furthermore, an existing stereocenter can control the stereochemistry of the three newly created stereocenters [Eq. (3)]. Table 1 Phosphine-catalyzed stereoselective synthesis of highly functionalized diquinanes at room temperature (20% P(n-Bu)3, CH2Cl2/EtOAc). (3) The diquinanes produced via our phosphine-catalyzed double cyclization process can be functionalized with high stereoselectivity. Thus, new stereocenters can be introduced at the α or the β position of the enone [Eq. (4) and Eq. (5)],[10] as well as at the carbonyl group itself [Eq. (6)]. (4) (5) (6) We have initiated an investigation of an enantioselective variant of this phosphine-catalyzed diquinane synthesis. We anticipated that this challenge might be comparatively difficult, due to issues such as the potential generation of mixtures of E/Z isomers in key intermediates and the distance between the phosphine subunit and the site(s) of carbon–carbon bond formation. In view of such complications, we were pleased to determine that phosphepine 3 can catalyze the synthesis of a diquinane with promising enantioselectivity [60% ee; Eq. (7)].[11,12,13] (7) We have begun to explore the application of our method to the synthesis of other classes of fused carbocycles. Hydrindanes are an important family of targets,[14] and in a preliminary study we have determined that, without separate optimization, the method that we developed for the formation of diquinanes can be employed for the generation of 6,5 ring systems with promising yield and excellent stereoselectivity [Eq. (8) and Eq. (9)]. (8) (9) In summary, building on a powerful but largely unexploited mode of reactivity discovered by Tomita (phosphine catalysis via conjugate addition then cross tautomerization of an unsaturated carbonyl compound), we have developed a versatile new method for the room-temperature synthesis of diquinanes from acyclic precursors, thereby generating two rings, three stereocenters, and an olefin with high selectivity. The products of the double cyclization can be derivatized with excellent diastereoselection into an array of highly functionalized compounds. Preliminary studies suggest that an enantioselective variant can be achieved and that the method can be applied to the synthesis of other fused ring systems. Future investigations will further explore the scope of novel modes of reactivity furnished by phosphines and other nucleophilic catalysts.

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