Discovery of a Series of 7-Azaindoles as Potent and Highly Selective CDK9 Inhibitors for Transient Target Engagement.

Optimization of a series of azabenzimidazoles identified from screening hit and the information gained from a co-crystal structure of the azabenzimidazole-based lead bound to CDK9 led to the discovery of azaindoles as highly potent and selective CDK9 inhibitors. With the goal of discovering a highly selective and potent CDK9 inhibitor administrated intravenously that would enable transient target engagement of CDK9 for the treatment of hematological malignancies, further optimization focusing on physicochemical and pharmacokinetic properties led to azaindoles and . These compounds are highly potent and selective CDK9 inhibitors having short half-lives in rodents, suitable physical properties for intravenous administration, and the potential to achieve profound but transient inhibition of CDK9 .

PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity.

PARP7 is a monoPARP that catalyzes the transfer of single units of ADP-ribose onto substrates to change their function. Here, we identify PARP7 as a negative regulator of nucleic acid sensing in tumor cells. Inhibition of PARP7 restores type I interferon (IFN) signaling responses to nucleic acids in tumor models.

A potent and selective PARP14 inhibitor decreases protumor macrophage gene expression and elicits inflammatory responses in tumor explants.

PARP14 has been implicated by genetic knockout studies to promote protumor macrophage polarization and suppress the antitumor inflammatory response due to its role in modulating interleukin-4 (IL-4) and interferon-γ signaling pathways. Here, we describe structure-based design efforts leading to the discovery of a potent and highly selective PARP14 chemical probe. RBN012759 inhibits PARP14 with a biochemical half-maximal inhibitory concentration of 0.

Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies.

A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound ), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound , a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9.

In Vitro and Cellular Probes to Study PARP Enzyme Target Engagement.

Poly(ADP-ribose) polymerase (PARP) enzymes use nicotinamide adenine dinucleotide (NAD) to modify up to seven different amino acids with a single mono(ADP-ribose) unit (MARylation deposited by PARP monoenzymes) or branched poly(ADP-ribose) polymers (PARylation deposited by PARP polyenzymes). To enable the development of tool compounds for PARP monoenzymes and polyenzymes, we have developed active site probes for use in in vitro and cellular biophysical assays to characterize active site-directed inhibitors that compete for NAD binding. These assays are agnostic of the protein substrate for each PARP, overcoming a general lack of knowledge around the substrates for these enzymes.

Discovery of (2)--[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a Potent and Selective Janus Kinase 1 Inhibitor.

JAK1, JAK2, JAK3, and TYK2 belong to the JAK (Janus kinase) family. They play critical roles in cytokine signaling. Constitutive activation of JAK/STAT pathways is associated with a wide variety of diseases.

Forced Self-Modification Assays as a Strategy to Screen MonoPARP Enzymes.

Mono(ADP-ribosylation) (MARylation) and poly(ADP-ribosylation) (PARylation) are posttranslational modifications found on multiple amino acids. There are 12 enzymatically active mono(ADP-ribose) polymerase (monoPARP) enzymes and 4 enzymatically active poly(ADP-ribose) polymerase (polyPARP) enzymes that use nicotinamide adenine dinucleotide (NAD) as the ADP-ribose donating substrate to generate these modifications. While there are approved drugs and clinical trials ongoing for the enzymes that perform PARylation, MARylation is gaining recognition for its role in immune function, inflammation, and cancer.

Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors.

Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and have thus been implicated in both cancer and inflammatory diseases. The JAK family consists of four highly homologous members: JAK1-3 and TYK2. The development of small-molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology.

Adventures in Scaffold Morphing: Discovery of Fused Ring Heterocyclic Checkpoint Kinase 1 (CHK1) Inhibitors.

Checkpoint kinase 1 (CHK1) inhibitors are potential cancer therapeutics that can be utilized for enhancing the efficacy of DNA damaging agents. Multiple small molecule CHK1 inhibitors from different chemical scaffolds have been developed and evaluated in clinical trials in combination with chemotherapeutics and radiation treatment. Scaffold morphing of thiophene carboxamide ureas (TCUs), such as AZD7762 (1) and a related series of triazoloquinolines (TZQs), led to the identification of fused-ring bicyclic CHK1 inhibitors, 7-carboxamide thienopyridines (7-CTPs), and 7-carboxamide indoles.

Structure-Cytotoxicity Relationships of Analogues of N-Desacetoxytubulysin H.

Herein we report structure-cytotoxicity relationships for analogues of N-desacetoxytubulyisn H 1. A novel synthetic approach toward 1 enabled the discovery of compounds with a range of activity. Calculated basicity of the N-terminus of tubulysins was shown to be a good predictor of cytotoxicity.

Identification of azabenzimidazoles as potent JAK1 selective inhibitors.

We have identified a class of azabenzimidazoles as potent and selective JAK1 inhibitors. Investigations into the SAR are presented along with the structural features required to achieve selectivity for JAK1 versus other JAK family members. An example from the series demonstrated highly selective inhibition of JAK1 versus JAK2 and JAK3, along with inhibition of pSTAT3 in vivo, enabling it to serve as a JAK1 selective tool compound to further probe the biology of JAK1 selective inhibitors.

Small molecule inhibitor of apoptosis proteins antagonists: a patent review.

Introduction: The family of inhibitor of apoptosis proteins (IAPs) plays a key role in the suppression of proapoptotic signaling; hence, a small molecule that disrupts the binding of IAPs with their functional partner should restore apoptotic response to proapoptotic stimuli in cells. The continued publication of new patent applications of IAP antagonists over the past 4 years is a testament to the continued interest surrounding the IAP family of proteins.

Areas Covered: This review summarizes the IAP antagonist patent literature from 2010 to 2014.

Discovery of a novel class of dimeric Smac mimetics as potent IAP antagonists resulting in a clinical candidate for the treatment of cancer (AZD5582).

A series of dimeric compounds based on the AVPI motif of Smac were designed and prepared as antagonists of the inhibitor of apoptosis proteins (IAPs). Optimization of cellular potency, physical properties, and pharmacokinetic parameters led to the identification of compound 14 (AZD5582), which binds potently to the BIR3 domains of cIAP1, cIAP2, and XIAP (IC50 = 15, 21, and 15 nM, respectively). This compound causes cIAP1 degradation and induces apoptosis in the MDA-MB-231 breast cancer cell line at subnanomolar concentrations in vitro.

Discovery and optimization of a novel series of potent mutant B-Raf(V600E) selective kinase inhibitors.

B-Raf represents an attractive target for anticancer therapy and the development of small molecule B-Raf inhibitors has delivered new therapies for metastatic melanoma patients. We have discovered a novel class of small molecules that inhibit mutant B-Raf(V600E) kinase activity both in vitro and in vivo. Investigations into the structure-activity relationships of the series are presented along with efforts to improve upon the cellular potency, solubility, and pharmacokinetic profile.

Discovery of checkpoint kinase inhibitor (S)-5-(3-fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide (AZD7762) by structure-based design and optimization of thiophenecarboxamide ureas.

Checkpoint kinases CHK1 and CHK2 are activated in response to DNA damage that results in cell cycle arrest, allowing sufficient time for DNA repair. Agents that lead to abrogation of such checkpoints have potential to increase the efficacy of such compounds as chemo- and radiotherapies. Thiophenecarboxamide ureas (TCUs) were identified as inhibitors of CHK1 by high throughput screening.

Discovery of a novel class of 2-ureido thiophene carboxamide checkpoint kinase inhibitors.

Checkpoint kinase-1 (Chk1, CHEK1) is a Ser/Thr protein kinase that mediates the cellular response to DNA-damage. A novel class of 2-ureido thiophene carboxamide urea (TCU) Chk1 inhibitors is described. Inhibitors in this chemotype were optimized for cellular potency and selectivity over Cdk1.

Dual catalyst control in the enantioselective intramolecular Morita-Baylis-Hillman reaction.

The intramolecular Morita-Baylis-Hillman (MBH) reaction has been achieved with unprecedented levels of enantioselectivity. Using a co-catalyst system involving pipecolinic acid and N-methylimidazole, cyclic MBH products have been obtained with enantiomer ratios of 92:8 (84% ee). In addition, reactions may be carried out with a "kinetic resolution quench" involving acetic anhydride and an asymmetric acylation catalyst such that ee enhancement occurs to deliver products with >98% ee with an isolated yield of 50%.

Peptide bond isosteres: ester or (E)-alkene in the backbone of the collagen triple helix.

[structure: see text] Collagen is the most abundant protein in animals. Interstrand N-H..

Dual catalyst control in the amino acid-peptide-catalyzed enantioselective Baylis-Hillman reaction.

[reaction: see text] Nucleophile-loaded peptides and proline have been found to function synergistically as cocatalysts for the asymmetric ketone-based Baylis-Hillman reaction. Although neither compound is effective independently in terms of rate or enantioselectivity, their combination leads to catalysis where enantioselectivities up to 81% have been observed.

Synthesis of the pro-gly dipeptide alkene isostere using olefin cross-metathesis.

An approach to the synthesis of dipeptide olefin isosteres using intermolecular olefin cross-metathesis is presented. In particular, a synthesis of the Pro-Gly isostere (1) is reported. Conversion of N-BOC-proline into the corresponding vinyl-substituted carbamate provides the N-terminal cross-metathesis partner (2).

Stereocontrol in Intermolecular Dirhodium(II)-Catalyzed Carbonyl Ylide Formation and Reactions. Dioxolanes and Dihydrofurans.

Ethyl diazoacetate undergoes dirhodium(II)-catalyzed reactions with aryl aldehydes to form 1,3-dioxolanes as mixtures of diastereoisomers in good yields. Carbonyl ylides are reaction intermediates. Catalyst dependent diastereocontrol is observed for reactions with p-nitrobenzaldehyde, but not for those with p-anisaldehyde or benzaldehyde, so that at least with transformations involving p-nitrobenzaldehyde a metal-stabilized ylide is responsible for product formation.

Incorporation of Peptide Isosteres into Enantioselective Peptide-Based Catalysts as Mechanistic Probes.

Olefinic analogues of effective peptide-based catalysts for the kinetic resolution of functionalized racemic secondary alcohols have been synthesized. The isosteric replacement of the peptide amide bond in 1 with an (E)-alkene to form 2 has enabled the evaluation of the kinetic role of particular amides within these catalysts.