Small Molecules inhibitor

Arkin MR, Wells JA (2004) Small-molecule inhibitors of protein-protein interactions progressing towards the dream. Nat Rev Drug Discov 3 301-331... 

Mayer TU, Kapoor TM, Haggarty SJ et al (1999) Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286 971... 

The most extensive development of pharmacological inhibitors of MAPK cascades members has been for p38 (Table 1) [3]. Small-molecule inhibitors have been developed for two p38 isoforms (a and (3). Pyridinyl imidazole compounds have been known to block inflammation since the early 1970s. Structural analyses have revealed that p38 kinase inhibitors binds to the ATP-binding pocket of p38 thereby acting as competitive inhibitors. The p38 kinase inhibitor SB202190 is able to bind both the low-activity nonphosphorylated... 

As illustrated in Fig. 2, these complexes are likely dimeric. Curiously, only when in TORC1 is TOR/mTOR bound and inhibited by the rapamycin-FKBP12 complex. Rapamycin has been an incredibly important tool to dissect the molecular function of TORC1/mTORCl and as outlined below, rapamycin and related derivatives have ever-increasing clinical potential. No small molecule inhibitor of TORC2/mTORC2 has been identified and consequently understood the functions of this complex is relatively less well developed. 

Though a large number of small molecule inhibitors against a variety of tyrosine kinases are being developed, the most advanced drugs can be roughly classified as (i) Bcr-Abl/Src family kinase inhibitors, (ii) ErbB inhibitors and (iii) broad spectrum TfCIs with an anti-angiogenic component. 

Bressanelli S, Tomei L, Rey FA, De Francesco R (2002) Stmctural analysis of the hepatitis C vims RNA polymerase in complex with ribonucleotides. J Virol 76 3482-3492 Burton G, Ku TW, Carr TJ, Kiesow T, Sarisky RT, Lin-Goerke J, Baker A, Eamshaw DL, Hofmann GA, Keenan RM, Dhanak D (2005) Identification of small molecule inhibitors of the hepatitis C vims RNA-dependent RNA polymerase from a pyrrolidine combinatorial mixture. Bioorg Med Chem Lett 15 1553-1556... 

Di Marco S, Volpari C, Tomei L, Altamura S, Harper S, Narjes F, Koch U, Rowley M, De Francesco R, Mighaccio G, Card A (2005) Interdomain communication in hepatitis C virus polymerase abolished by small molecule inhibitors bound to a novel allosteric site. J Biol Chem 280 29765-29770... 

Gao Y, Dickerson JB, Guo F, Zheng J, Zheng Y. Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci USA 2004 101 7618-23. 

Fragment screening by NMR was applied recently in the search of non-peptidic small molecule inhibitors. Two scaffolds (13) and (14), which bind the enzyme at the S1-S3 and the S2 binding site respectively, as shown by chemical shift perturbation, were linked together to yield competitive inhibitors such as (15) with micromolar IC50 values [158]. There have been no reports of non-peptidic inhibitors with potency and pharmacokinetics similar to the peptidic or peptidomimetic inhibitors described above. 

Despite the complexity of the experiments and the enormous data manipulation necessary, complex biological pathways, as well as new drug targets are being identified by this method. Examples include screens for compounds that arrest cells in mitosis, that block cell migration, and that block the secretory pathway [50], or assays with primary T cells from PLP TCR transgenic mice for their inhibitory activity on the proliferation and secretion of proinflammatory cytokines in PLP-reactive T cells [51], and identification of small-molecule inhibitors of histone acetyltransferase activity [52]. 

There are more than 100 different types of tyrosine kinases present in the body. Sometimes tyrosine kinase inhibitors are referred to as small-molecule inhibitors. Each of the following drugs was developed to block either several or a specific tyrosine kinase. 

Dorr P, Westby M, Dobbs S, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Anti-microb Agents Chemother 2005 49(l 1 ) 4721 —4732. 

To account for differences in the Hill coefficient, enzyme inhibition data are best ht to Equation (5.4) or (5.5). In measuring the concentration-response function for small molecule inhibitors of most target enzymes, one will hnd that the majority of compounds display Hill coefficient close to unity. However, it is not uncommon to hnd examples of individual compounds for which the Hill coefficient is signihcandy greater than or less than unity. When this occurs, the cause of the deviation from expected behavior is often reflective of non-ideal behavior of the compound, rather than a true reflection of some fundamental mechanism of enzyme-inhibitor interactions. Some common causes for such behavior are presented below. 

While the role of PHD inhibitors in the treatment of anemia is now validated, therapeutic validation is less certain in other HIF-associated pathologies such as wound healing, ulcerative colitis, therapeutic angiogenesis, and treatment of acute ischemic events such as myocardial ischemia and stroke. All of these indications are supported by a compelling array of in vitro and in vivo preclinical studies but their utility in the clinical setting remains to be evaluated and represents exciting possibilities for the future of small-molecule inhibitors of PHD enzymes. 

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