Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors

Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1 active site, it was hypothesized that the affinity of the indolylquinolinone series (2) for Chek1 kinase would be improved via C6 substitution into the hydrophobic region I (HI) pocket. An efficient route to 6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly optimized for potency by modification at C6. A general trend was observed among these low nanomolar Chek1 inhibitors that compounds with multiple basic amines, or elevated polar surface area (PSA) exhibited poor cell potency. Minimization of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with improved cell potency, and preliminary pharmacokinetic data are presented for several of these compounds.     

Discovering novel 7-azaindole-based series as potent AXL kinase inhibitors

AXL is a receptor tyrosine kinase that plays a key role in tumor growth and proliferation. The scientific community has validated AXL as therapeutic target in the treatment of cancers for several years now, and several AXL inhibitors have been developed but none of them are approved. In this context, we started to design new kinase inhibitors targeting AXL from the 7-azaindole scaffold well known to interact with the ATP binding site of the kinase. Focused screening and chemical diversification around 7-azaindole scaffold were developed, based on modeling studies and medicinal chemistry rational, leading to the discovery of a new family of hits with potent inhibitory activity against AXL.     

Novel series of pyrrolotriazine analogs as highly potent pan-Aurora kinase inhibitors

The synthesis and SAR for a novel series of pyrrolotriazines as pan-Aurora kinase inhibitors are described. Optimization of the cyclopropane carboxamide terminus of lead compound 1 resulted in analogs with high cellular activity and improved rat PK profiles. Notably, compound 17l demonstrated tumor growth inhibition in a mouse xenograft model.     

Heterobiaryl purine derivatives as potent antiproliferative agents: Inhibitors of cyclin dependent kinases. Part II

C-6 Biarylmethylamino purine derivatives of roscovitine (1) inhibit cyclin dependent kinases and demonstrate potent antiproliferative activity. Replacement of the aryl rings of the C-6 biarylmethylamino group with heterobiaryl rings has provided compounds with significantly improved activity. In particular, derivatives 18g and 9c demonstrated 1000-fold and 1250-fold improvements, respectively, in the growth inhibition of HeLa cells compared to roscovitine (1).     

Biaryl purine derivatives as potent antiproliferative agents: Inhibitors of cyclin dependent kinases. Part I

The introduction of an aryl ring onto the 4-position of the C-6 benzyl amino group of the Cdk inhibitor roscovitine (2), maintained the potent Cdk inhibition demonstrated by roscovitine (2) as well as greatly improving the antiproliferative activity. A series of C-6 biarylmethylamino derivatives was prepared addressing modifications on the C-6 biaryl rings, N-9 and C-2 positions to provide compounds that displayed potent cytotoxic activity against tumor cell lines. In particular, derivative 21h demonstrated a >750-fold improvement in the growth inhibition of HeLa cells compared to roscovitine (2).     

2-Aminobenzimidazoles as potent Aurora kinase inhibitors

This Letter describes the discovery and key structure–activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.     

A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6 ligands

A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6 ligands is reported.     

Identification of protein kinase CK2 as a potent kinase of Epstein-Barr virus latent membrane protein 1

The C-terminus of latent membrane protein 1 (LMP1) can be phosphorylated in vivo. However, the protein kinase responsible for LMP1 phosphorylation has not yet been identified. In this study, GST fusion proteins containing the C-terminus of LMP1 were generated and used as substrates to survey the kinases that phosphorylate LMP1. Among several purified protein kinases tested, only protein kinase CK2 (CK2) could specifically phosphorylate LMP1. Using the in-gel kinase assay in the absence and presence of a selective CK2 inhibitor, 4,5,6,7-tetrabromobenzotriazole, CK2 was determined to be the major kinase to phosphorylate LMP1 in lymphoma and epithelial cell lines. This is the first study to show that CK2 is a potent kinase to phosphorylate LMP1 in vitro.     

Identification of a series of benzoxazoles as potent 5-HT6 ligands

As part of our continuing efforts to identify therapeutics for CNS diseases such as schizophrenia and Alzheimer’s disease (AD), we have been focused on the 5-HT₆ receptor in order to identify potent and selective ligands as a potential treatment for cognitive dysfunction. Herein we report the identification of a novel series of benzoxazole derivatives as potent 5-HT₆ ligands. The synthesis and detailed SAR of this class of compounds are reported. The compounds have been shown to be full antagonists in a cyclic AMP functional assay.     

4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors

Members of a novel class of 4-amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones were identified as potent dual ErbB-2/EGFR kinase inhibitors using concept-guided design approach. These compounds inhibited the growth of ErbB-2 over-expressing human tumor cell lines (BT474, N87, and SK-BR-3) in vitro. Compound 15 emerged as a key lead and showed significant ability to inhibit growth factor-induced receptor phosphorylation in SK-BR-3 cells (IC(50)=54 nM) and cellular proliferation in vitro (IC(50)=14, 58, and 58 nM for BT474, N87, and SK-BR-3 respectively). The X-ray co-crystal structure of EGFR with a close analog (17) was determined and validated our design rationale.     

Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors

A pyrrolopyridinyl thiophene carboxamide 7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of 7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3β.     

Characterization of TAE684 as a potent LRRK2 kinase inhibitor

Leucine-rich repeat kinase 2 (LRRK2) is linked to Parkinson's disease and may represent an attractive therapeutic target. Here we report a 2,4-dianilino-5-chloro-pyrimidine, TAE684, a previously reported inhibitor of anaplastic lymphoma kinase (ALK), is also a potent inhibitor of LRRK2 kinase activity (IC(50) of 7.8nM against wild-type LRRK2, 6.1nM against the G2019S mutant). TAE684 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3μM in cells and in mouse spleen and kidney, but not in brain, following oral doses of 10mg/kg.     

Novel imidazole compounds as a new series of potent,orally active inhibitors of 5-lipoxygenase

Replacement of the dihydroquinolinone pharmacophore of Zeneca's ZD2138 by ionizable imidazolylphenyl moiety has lead to the discovery of a novel series of potent and orally active 5-lipoxygenase (5-LO) inhibitors. The synthesis and structure-activity relationship (SAR) of this series of compounds are described herein.     

Aminofurazans as potent inhibitors of AKT kinase

AKT inhibitors containing an imidazopyridine aminofurazan scaffold have been optimized. We have previously disclosed identification of the AKT inhibitor GSK690693, which has been evaluated in clinical trials in cancer patients. Herein we describe recent efforts focusing on investigating a distinct region of this scaffold that have afforded compounds (30 and 32) with comparable activity profiles to that of GSK690693.     

A new series of neutral 5-substituted 4-anilinoquinazolines as potent, orally active inhibitors of erbB2 receptor tyrosine kinase

Starting from initial lead 1 containing a basic 5-substituent, optimisation of the glycolamide-derived neutral 5-substituent led to potent inhibitors of erbB2 with good pharmacokinetics. Representative compounds 19 and 21 inhibited phosphorylation of erbB2 in a mouse BT474C xenograft model after oral administration.     

Novel pyrrolyllactone and pyrrolyllactam indolinones as potent cyclin-dependent kinase 2 inhibitors

Cyclin-dependent kinases (CDKs) are essential in the control of cell cycle progression. Inhibition of CDKs represents a new approach for pharmacological intervention in the treatment of a variety of proliferative diseases, especially cancer. Based on the crystal structure of CDK2 in complex with an imidazole indolinone compound 1 (SU9516), lead optimization through modeling, synthesis, and SAR studies has led to the discovery of a novel series of pyrrolyllactone and pyrrolyllactam indolinones as potent CDK2 inhibitors.     

Discovery of 2-amino-6-carboxamidobenzothiazoles as potent Lck inhibitors

A novel series of 2-amino-6-carboxamidobenzothiazole was discovered to have potent Lck inhibitory properties. A highly efficient chemistry was developed. Also described are the detailed SAR study and the BaF3 cell line profiling for this series.     

Identification of a novel series of potent and selective CCR6 inhibitors as biological probes

CCR6 has been implicated in both autoimmune diseases and non-autoimmune diseases. Thus, inhibition of CCR6-dependent cell migration is an attractive strategy for their treatment. An orally available small molecule inhibitor of CCR6 could therefore be a useful biological probe for the pathophysiological studies. Initial SAR study of a hit compound provided potent N-benzenesulfonylpiperidine derivatives that suppressed CCL20-induced Gi signals. By subsequent scaffold morphing of the central ring and further optimization, we identified a novel series of 1,4-trans-1-benzenesulfonyl-4-aminocyclohexanes as potent and selective CCR6 inhibitors with good pharmacokinetic properties. Our compounds showed good correlation between Gi signal inhibitory activity and cell migration inhibitory activity in human CCR6-transfected CHO cells. In addition, representative compound 35 potently inhibited CCR6-dependent cell migration and the increase in ERK phosphorylation in human primary cells. Therefore, the compound could be used effectively as a biological probe against human CCR6.     

2-Amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists

Blockade of the P2Y₁ receptor is important to the treatment of thrombosis with potentially improved safety margins compared with P2Y₁₂ receptor antagonists. Investigation of a series of urea surrogates of the diaryl urea lead 3 led to the discovery of 2-amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y₁ receptor antagonists, among which compound 5a was the most potent and the first non-urea analog with platelet aggregation (PA) IC₅₀ less than 0.5 μM with 10 μM ADP. Several 2-amino-1,3,4-thiadiazole analogs such as 5b and 5f had a more favorable pharmacokinetic profile, such as higher C_trough, lower Cl, smaller Vdss, and similar bioavailability compared with 3.     

4-Anilino-7-alkenylquinoline-3-carbonitriles as potent MEK1 kinase inhibitors

A series of substituted 7-alkenyl 4[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-3-quinolinecarbonitrile analogs were synthesized and evaluated as MEK1 kinase inhibitors. The synthetic details, structure-activity relationships, biological activity, and selected oral exposure studies of these analogs are described. From these studies, compound 5m was chosen as a strong candidate for further evaluation. The selectivity of 5m was ascertained against a panel of 17 kinases, where activity was observed against EGFR, Src, Lyn, and IR kinases. Western blot studies in WM-266 cells demonstrated that 5m inhibited phosphorylation of ERK, while additional kinase pathways tested showed no inhibition at up to 10 microM of 5 m. PK studies, as well as a xenograft and in vivo biomarker studies are described for 5m.