Knowledge-based design of 7-azaindoles as selective B-Raf inhibitors

Tang, Jun; Hamajima, Toshihiro; Nakano, Masato; Sato, Hideyuki; Dickerson, Scott H.; Lackey, Karen

doi:10.1016/j.bmcl.2008.07.019

Cited by 31 publications

(12 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The targeted approach to cancer therapy development has been validated by the growing number of marketed small-molecule protein kinase inhibitors . Although there are no approved kinase inhibitors that are selective for B-Raf V600E , four are currently in clinical trials including RAF265 (Chiron/Novartis), XL281/BMS-908662 (Exelixis/BMS), GSK2118436 (GlaxoSmithKline), and PLX4032 ( 1 , Plexxikon/Roche), with others in preclinical development. − A detailed account of the discovery and clinical development of 1 , a selective B-Raf V600E inhibitor that binds to the active conformation of the kinase (DFG-in), has recently been published . The authors report that the propyl group of the sulfonamide effects B-Raf V600E selectivity by trapping a small lipophilic pocket enlarged by an outward shift of the αC-helix .…”

mentioning

confidence: 99%

Pyrazolopyridine Inhibitors of B-Raf^V600E. Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors

Wenglowsky

Ren

Ahrendt

et al. 2011

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

The V600E mutation of B-Raf kinase results in constitutive activation of the MAPK signaling pathway and is present in approximately 7% of all cancers. Using structure-based design, a novel series of pyrazolopyridine inhibitors of B-Raf(V600E) was developed. Optimization led to the identification of 3-methoxy pyrazolopyridines 17 and 19, potent, selective, and orally bioavailable agents that inhibited tumor growth in a mouse xenograft model driven by B-Raf(V600E) with no effect on body weight. On the basis of their in vivo efficacy and preliminary safety profiles, 17 and 19 were selected for further preclinical evaluation.

show abstract

mentioning

confidence: 99%

Pyrazolopyridine Inhibitors of B-Raf^V600E. Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors

Wenglowsky

Ren

Ahrendt

et al. 2011

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

show abstract

“…The compound (37), shows excellent potency in both enzyme and cellular assays with IC 50 values of 2.5 and 63 nM, respectively. It exhibits also a high selectivity against other kinases [68]. Fig.…”

Section: Other Structuresmentioning

confidence: 97%

Non-ATP Competitive Protein Kinase Inhibitors

Garuti¹,

Roberti²,

Bottegoni

2010

CMC

110

View full text Add to dashboard Cite

Protein kinases represent an attractive target in oncology drug discovery. Most of kinase inhibitors are ATP-competitive and are called type I inhibitors. The ATP-binding pocket is highly conserved among members of the kinase family and it is difficult to find selective agents. Moreover, the ATP-competitive inhibitors must compete with high intracellular ATP levels leading to a discrepancy between IC50s measured by biochemical versus cellular assays. The non-ATP competitive inhibitors, called type II and type III inhibitors, offer the possibility to overcome these problems. These inhibitors act by inducing a conformational shift in the target enzyme such that the kinase is no longer able to function. In the DFG-out form, the phenylalanine side chain moves to a new position. This movement creates a hydrophobic pocket available for occupation by the inhibitor. Some common features are present in these inhibitors. They contain a heterocyclic system that forms one or two hydrogen bonds with the kinase hinge residue. They also contain a hydrophobic moiety that occupies the pocket formed by the shift of phenylalanine from the DFG motif. Moreover, all the inhibitors bear a hydrogen bond donor-acceptor pair, usually urea or amide, that links the hinge-binding portion to the hydrophobic moiety and interacts with the allosteric site. Examples of non ATP-competitive inhibitors are available for various kinases. In this review small molecules capable of inducing the DFG-out conformation are reported, especially focusing on structural feature, SAR and biological properties.

show abstract

“…Our group has previously reported the synthesis of 4-azaindoles derivatives which target DYRK1A as well as B-Raf kinase in the sub nanomolar range (see Scheme 15) [77]. The use of a 7-azaindole scaffold in the search for a novel series of selective B-Raf inhibitors has also been described in the literature [109]. A 2-D pharmacophore map depicting the seven critical binding regions of the ATP-binding domain was used for the design of a new 7-azaindole series by incorporating functional groups that could interact with the key features of these regions.…”

Section: B-raf Kinase Inhibitorsmentioning

confidence: 99%

The Azaindole Framework in the Design of Kinase Inhibitors

et al. 2014

View full text Add to dashboard Cite

This review article illustrates the growing use of azaindole derivatives as kinase inhibitors and their contribution to drug discovery and innovation. The different protein kinases which have served as targets and the known molecules which have emerged from medicinal chemistry and Fragment-Based Drug Discovery (FBDD) programs are presented. The various synthetic routes used to access these compounds and the chemical pathways leading to their synthesis are also discussed. An analysis of their mode of binding based on X-ray crystallography data gives structural insights for the design of more potent and selective inhibitors.

show abstract

Knowledge-based design of 7-azaindoles as selective B-Raf inhibitors

Cited by 31 publications

References 14 publications

Pyrazolopyridine Inhibitors of B-Raf^V600E. Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors

Pyrazolopyridine Inhibitors of B-Raf^V600E. Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors

Non-ATP Competitive Protein Kinase Inhibitors

The Azaindole Framework in the Design of Kinase Inhibitors

Contact Info

Product

Resources

About

Knowledge-based design of 7-azaindoles as selective B-Raf inhibitors

Cited by 31 publications

References 14 publications

Pyrazolopyridine Inhibitors of B-RafV600E. Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors

Pyrazolopyridine Inhibitors of B-RafV600E. Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors

Non-ATP Competitive Protein Kinase Inhibitors

The Azaindole Framework in the Design of Kinase Inhibitors

Contact Info

Product

Resources

About

Pyrazolopyridine Inhibitors of B-Raf^V600E. Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors

Pyrazolopyridine Inhibitors of B-Raf^V600E. Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors