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  • van Linden et al developed a comprehensive guide

    2020-03-26

    van Linden et al. developed a comprehensive guide that describes drug and ligand binding to more than 1200 human and mouse protein kinase domains [77]. Their KLIFS (kinase–ligand interaction fingerprint and structure) directory includes an alignment of 85 potential ligand binding-site residues occurring in both the amino-terminal and carboxyterminal lobes; this directory facilitates the classification of drugs and ligands based upon their binding characteristics and expedites the detection of related interactions. Furthermore, these authors devised a standard amino KN-93 hydrochloride residue numbering system that helps in the comparison of many protein kinases. Table 3 specifies the correspondence between the KLIFS database residue numbers and the catalytic spine, shell, and regulatory spine amino acid residue nomenclature. Furthermore, these investigators established a valuable free and searchable web site that is regularly updated thereby providing comprehensive information on the interaction of protein kinases with drugs and ligands (klifs.vu-compmedchem.nl/). Additionally, Carles et al. developed a comprehensive directory of protein kinase inhibitors in clinical trials [82]. They established a free and searchable web site that is regularly updated which includes inhibitor structures and their physical properties, protein kinase targets, therapeutic indications, year of first approval (if applicable), and trade name (http://www.icoa.fr/pkidb/). The Blue Ridge Insitute for Medical Research website (www.brimr.org/PKI/PKIs.htm), which is regularly updated, depicts the structures and properties of all FDA-approved protein kinase inhibitors.
    Selected CDK inhibitors that are FDA approved or in clinical trials Palbociclib is a CDK4/6 antagonist that in combination with the aromatase antagonist letrozole is FDA-approved for (i) the treatment of postmenopausal women with ER+/HER2– advanced breast cancer as an initial, or first-line, endocrine-based therapy for metastatic disease or (ii) as a second-line treatment in combination with fulvestrant in women with disease progression following endocrine therapy (www.brimr.org/PKI/PKIs.htm). See Refs. [[83], [84], [85], [86]] for a summary of the preclinical studies and clinical trials that led to these approvals. The scaffold of palbociclib consists of a pyrido[2,3-d] pyrimidinone core (Fig. 6A); this orally effective agent inhibits CDK4-cyclin D1 (IC50 value 11 nM), CDK4-cyclin D3 (9 nM), and CDK6-cyclin D2 (15 nM) [87]. It is not effective against CDK2-cyclin E2, CDK2-cyclin A, and CDK1-cyclin B (IC50 values exceeding 10 μM). During the development of this compound, VanderWel et al. found that the addition of the cyclopentyl group at N8 of the pyrido[2,3-d] pyrimidinone core provided an optimal combination of potency and selectivity for CDK4/6 [88]. Moreover, the addition of the C5 methyl group decreased CDK1/2 inhibition by these derivatives while they remained effective against CDK4/6. Toogood et al. from the same laboratory discovered that including the 2-aminopyridine on the C2 of the scaffold increased selectivity for CDK4/6 in vitro [89]. Furthermore, the addition of the acetyl group at C6 maintained the selectivity toward CDK4/6. The X-ray crystal structure of palbociclib bound to the complex of CDK6-cyclin V (a K type cyclin) shows that a hydrogen bond forms between the 2-amino group attached to the pyridopyrimidine scaffold and the carbonyl group of V101 of the hinge of the enzyme (Fig. 7A). Cyclin V is a K-type cyclin that is a gene product of Kaposi sarcoma-associated herpesvirus that activates CDK6. A second hydrogen bond forms between the N3 nitrogen of the palbociclib scaffold and the NH group of V101 while a third hydrogen bond forms between the 6-acetyl carbonyl group and the DFG-D163 NH group. The 5-methyl and 6-acetyl groups are found within hydrophobic pocket BPIA in the gate area [53,77] while the C2 piperazinylpyridinylamino group extends into the solvent. Palbociclib makes numerous hydrophobic contacts with the enzyme including interactions with the β1-strand I19, the β2-strand V27 (CS7), the β3-strand A41 (CS8) and K43 (of the AxK signature), V77 (Sh1) within the αC-β4 loop, the F98 gatekeeper (Sh2), the second hinge residue (H100), Q103 and D104 proximal to the αD-helix, Q149 and N150 within the catalytic loop, the β7-strand L152 (CS6), and A162, which occurs just before DFG-D163 of the activation segment (the x of xDFG). The N8 cyclopentyl group occupies the space where the ribose of ATP normally occurs. The drug binds to an active conformation of the CDK6-cyclin V complex (αCin, open activation segment, linear R-spine) and is thus a type I inhibitor [53].