Alexander M. Taylor

Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637).

CBP and EP300 are highly homologous, bromodomain-containing transcription coactivators involved in numerous cellular pathways relevant to oncology. As part of our effort to explore the potential therapeutic implications of selectively targeting bromodomains, we set out to identify a CBP/EP300 bromodomain inhibitor that was potent both in vitro and in cellular target engagement assays and was selective over the other members of the bromodomain family. Reported here is a series of cell-potent and selective probes of the CBP/EP300 bromodomains, derived from the fragment screening hit 4-methyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-one.

A Practical Synthesis of Indoles via a Pd-Catalyzed C−N Ring Formation

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.

Development of methyl isoxazoleazepines as inhibitors of BET

In this report we detail the evolution of our previously reported thiophene isoxazole BET inhibitor chemotype exemplified by CPI-3 to a novel bromodomain selective chemotype (the methyl isoxazoleazepine chemotype) exemplified by carboxamide 23. The methyl isoxazoleazepine chemotype provides potent inhibition of the bromodomains of the BET family, excellent in vivo PK across species, low unbound clearance, and target engagement in a MYC PK-PD model.

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.

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 benzo[b]isoxazolo[4,5-d]azepines and benzotriazolo[4,3-d][1,4]diazepines 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.

GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2)

The biological function of bromodomains, epigenetic readers of acetylated lysine residues, remains largely unknown. Herein we report our efforts to discover a potent and selective inhibitor of the bromodomain of cat eye syndrome chromosome region candidate 2 (CECR2). Screening of our internal medicinal chemistry collection led to the identification of a pyrrolopyridone chemical lead, and subsequent structure-based drug design led to a potent and selective CECR2 bromodomain inhibitor (GNE-886) suitable for use as an in vitro tool compound.

GNE-371, a Potent and Selective Chemical Probe for the Second Bromodomains of Human Transcription-Initiation-Factor TFIID Subunit 1 and Transcription-Initiation-Factor TFIID Subunit 1-like

The biological functions of the dual bromodomains of human transcription-initiation-factor TFIID subunit 1 (TAF1(1,2)) remain unknown, although TAF1 has been identified as a potential target for oncology research. Here, we describe the discovery of a potent and selective in vitro tool compound for TAF1(2), starting from a previously reported lead. A cocrystal structure of lead compound 2 bound to TAF1(2) enabled structure-based design and structure-activity-relationship studies that ultimately led to our in vitro tool compound, 27 (GNE-371). Compound 27 binds TAF1(2) with an IC50 of 10 nM while maintaining excellent selectivity over other bromodomain-family members. Compound 27 is also active in a cellular-TAF1(2) target-engagement assay (IC50 = 38 nM) and exhibits antiproliferative synergy with the BET inhibitor JQ1, suggesting engagement of endogenous TAF1 by 27 and further supporting the use of 27 in mechanistic and target-validation studies.

Abstract A20: A leukemic model of acquired resistance to BET inhibition reveals a role for CBP/EP300 bromodomains in the regulation of c-MYC expression

Pharmacological modulation of c-MYC expression has recently become possible through small molecule engagement of the BET bromodomain proteins. As multiple BET inhibitors (BETi) progress through clinical trials, understanding possible mechanisms of acquired resistance becomes imperative to maximize therapeutic efficacy, assess possible drug combination strategies, and identify characteristics of next generation BET inhibitors. In the present study, we describe a cellular model of BETi resistance, which demonstrates a significantly blunted phenotypic and molecular response to BETi. The expression of c-MYC mRNA, highly susceptible to BETi in the parental cells, is restored in resistant cells through transcriptional bypass of BET-mediated co-activation. Through the use of a novel CBP/EP300 bromodomain inhibitor (CBP/EP300i), we show that c-MYC expression in BETi-resistant cells is dependent on CBP/EP300 bromodomain function, and that co-treatment with CBP/EP300i restores phenotypic sensitivity. CBP/EP300i was additionally found to transcriptionally silence MYC expression in numerous myeloma and leukemia derived cell lines in a manner comparable to BETi, identifying a novel modality to pharmacologically target the MYC oncogenic axis. While both BET and CBP/EP300 bromodomains regulate the expression of MYC, their transcriptional and phenotypic effects are otherwise distinct, suggesting that CBP/EP300 bromodomain inhibition may represent an alternative or complementary therapeutic option to BET bromodomain inhibition. Citation Format: Andrew R. Conery, Richard C. Centore, Charlie Hatton, Adrianne Neiss, Hon-Ren Huang, Patricia J. Keller, Alexander M. Taylor, Alexandre Cote, Michael C. Hewitt, Christopher G. Nasveschuk, Yves Leblanc, Shihua Yao, Eneida Pardo, Laura Zawadzke, Florence Poy, Hari Jayaram, Shivangi Joshi, Peter Sandy, Anthony Romero, Terry Crawford, Richard Pastor, Tommy Lai, Kevin Chen, Jian Wang, Steven Magnuson, Brian K. Albrecht, Steve Bellon, Barbara M. Bryant, Robert J. Sims, III. A leukemic model of acquired resistance to BET inhibition reveals a role for CBP/EP300 bromodomains in the regulation of c-MYC expression. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A20.