9 research outputs found
A Design of Experiments Approach to a Robust Final Deprotection and Reactive Crystallization of IPI-926, A Novel Hedgehog Pathway Inhibitor
A design of experiments (DoE) approach
was taken to optimize purity
and reaction yield of the final debenzylation and hydrochloride salt
formation of IPI-926. The study involved a careful dissection of the
different process steps to enable an independent investigation of
these steps while ensuring that process streams were representative.
The results enabled a streamlined process from the final chemical
transformation to the salting and isolation and led to the elimination
of variability in the process as well as a robust control of impurities.
The optimized process was applied to production and demonstrated on
the kilogram scale
A Practical Synthesis of Indoles via a Pd-Catalyzed CāN Ring Formation
A method for the
synthesis of <i>N</i>-functionalized
C2-/C3-substituted indoles via Pd-catalyzed CāN bond coupling
of halo-aryl enamines is described. The general strategy utilizes
a variety of amines and Ī²-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
Discovery of Benzotriazolo[4,3ā<i>d</i>][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 <i>in vivo</i>, markers that
are of therapeutic relevance to cancer and inflammatory disease, respectively.
Herein we report substituted benzoĀ[<i>b</i>]ĀisoxazoloĀ[4,5-<i>d</i>]Āazepines and benzotriazoloĀ[4,3-<i>d</i>]Ā[1,4]Ādiazepines
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
Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors
The identification of a novel series
of small molecule BET inhibitors is described. Using crystallographic
binding modes of an amino-isoxazole fragment and known BET inhibitors,
a structure-based drug design effort lead to a novel isoxazole azepine
scaffold. This scaffold showed good potency in biochemical and cellular
assays and oral activity in an in vivo model of BET inhibition
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-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
Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains
The
biological role played by non-BET bromodomains remains poorly understood,
and it is therefore imperative to identify potent and highly selective
inhibitors to effectively explore the biology of individual bromodomain
proteins. A ligand-efficient nonselective bromodomain inhibitor was
identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic
substituents replacing the <i>N</i>-methyl group were designed
directing toward the conserved bromodomain water pocket, and two distinct
binding conformations were then observed. The substituents either
directly displaced and rearranged the conserved solvent network, as
in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent
to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct
substituents for individual bromodomains provided selectivity handles
useful for future lead optimization efforts for selective BRD9, CECR2,
and TAF1(2) inhibitors
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 <i>in vitro</i> 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-2<i>H</i>-benzoĀ[<i>b</i>]Ā[1,4]Ādiazepin-2-one
Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300
The single bromodomain of the closely
related transcriptional regulators
CBP/EP300 is a target of much recent interest in cancer and immune
system regulation. A co-crystal structure of a ligand-efficient screening
hit and the CBP bromodomain guided initial design targeting the LPF
shelf, ZA loop, and acetylated lysine binding regions. Structureāactivity
relationship studies allowed us to identify a more potent analogue.
Optimization of permeability and microsomal stability and subsequent
improvement of mouse hepatocyte stability afforded <b>59</b> (GNE-272, TR-FRET IC<sub>50</sub> = 0.02 Ī¼M, BRET IC<sub>50</sub> = 0.41 Ī¼M, BRD4(1) IC<sub>50</sub> = 13 Ī¼M) that retained
the best balance of cell potency, selectivity, and in vivo PK. Compound <b>59</b> showed a marked antiproliferative effect in hematologic
cancer cell lines and modulates <i>MYC</i> expression in
vivo that corresponds with antitumor activity in an AML tumor model