ATP-competitive inhibitors

Staurosporine analogs (5) and the 4-anilinoquinazolines and closely related structures (6) are the most represented kinase templates in these trials. 

Conformational restriction of the activation loop clearly comes at the cost of binding free energy (negative entropy), which is compensated for by the numerous 

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The abundance of structural information has led to a significant increase in the use of structure-based methods both to identify and to optimise inhibitors of protein kinases. The focus to date has centred upon small molecule ATP-competitive inhibitors and there are numerous examples of protein-ligand complexes available to guide design strategies. ATP binds in the cleft formed between the N- and C-terminal lobes of the protein kinase, forming several key interactions conserved across the protein kinase family. The adenine moiety lies in a hydrophobic region between the jS-sheet structure of subdomains I and II and residues from subdomains V and VIb. A... 

AS601245 has been reported to be an ATP-competitive inhibitor of JNK1, 2 and 3 with IC50 values = 150, 220 and 70 nM, respectively, with minimal to no activity in a panel of 25 other kinases [48]. In Jurkat T-cells, AS601245 at 10 pM inhibited IL-2 production induced by phorbol-12-myristate-l 3-acetate (PMA) by 90%. The weaker cell activity could be due to poor cell permeability. The oral bioavailability of AS601245 in rats was 38%. In mice, AS601245, when dosed at 60 mg/kg p.o. in a developed arthritis model induced by collagen, showed... 

Sorafenib is a reversible ATP-competitive inhibitor of multiple kinases developed by Bayer and Onyx. It was originally described as a C-Raf inhibitor, but has since been reported to inhibit B-Raf, p38a, KDR, and a several other... 

Although less explored, drug discovery efforts have also been directed to modulate IGF-IR kinase activity by compounds that do not necessarily interact with the ATP-binding cleft. Initial attempts to inhibit IGF-IR enzymatic activity with non-ATP competitive inhibitors resulted in the identification of several tyrphostin-type compounds (e.g., compound 4, Fig. 2) that showed weak activity in blocking IGF-IR autophosphorylation (IC50 7-13 p.M), but... 

Also related to Src kinase structural biology have been studies on two SFKs, namely Lck and Fyn. Importantly, the X-ray structure of Lck kinase was the first SFK determined [64] as complexes with AMP-PNP, staurosporine and PP2. Furthermore, a Fyn kinase-staurosporine complex has been recently described [65]. Extrapolating from the above Src kinase inhibitor crystal structures with respect to the hydrophobic specificity pocket and the active conformation of the protein to bind ATP-competitive inhibitors of varying templates and functional group elaboration, a working hypothesis of known Src kinase inhibitors (vide infra) can be suggested (Fig. 4). 

The remainder of this work will focus on the approaches to designing and identifying new inhibitors of Bcr-Abl including (1) more potent analogs of imatinib (2) non-ATP competitive inhibitors of Bcr-Abl and (3) dual inhibitors of both Bcr-Abl and members of the Src family of kinases (SFKs) that bind to the active form of Bcr-Abl. The status of the new Bcr-Abl inhibitors currently in the chnic will be summarized. 

Protein kinases can be classified according to the amino acid residue that is phosphorylated in the cellular process. Consequently, there are tyrosine-specific kinases and serine/threonine kinases. Tyrosine kinases are a family of tightly regulated enzymes, and the aberrant activation of various members of this family is one of the hallmarks of cancer. Tyrosine phosphorylation has been linked to multiple cell growth and differentiation pathways. Imatinib mesylate (1) is a tyrosine kinase inhibitor (TKI). An important characteristic of imatinib mesylate (1) is that it is an ATP-competitive inhibitor. It binds at the ATP binding site and blocks ATP binding thereby inhibiting kinase activities. 

The azepane-ring containing metabolite (—)-balanol, 349, from the fungus Verticillium balanoides <1993JA6452, 1994JAN639>, was found to be a potent ATP-competitive inhibitor of the protein kinase A (PKA) (Ki = 3.9nM)... 

As demonstrated by these marketed anticancer drugs, ATP competitive inhibitors are generally not as selective as people had thought however, inhibition of multiple kinases appears to be manageable and potentially an advantage when applied to the treatment of cancer. 

Today 23 ATP-competitive inhibitors for which structures have been disclosed are under clinical evaluation (5 in phase 1 clinical trials, 14 in phase 2,4 in phase 3), and Iressa was recently approved by the U. S. FDA (see Figure 7.1 and Table 7.1). 

Figure 7.15 Traxler s binding model for ATP-competitive inhibitors.

The similarities concerning the bound cofactors, the reaction mechanism, and the adenine-binding pockets led to a screen of the above-described purine-based library of ATP-competitive inhibitors originally designed to target CDKs for crossreactivity with the carbohydrate sulfotransferase NodH from Rhizobium meliloti. 

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