Invited ReviewThe role of small molecule Flt3 receptor protein-tyrosine kinase inhibitors in the treatment of Flt3-positive acute myelogenous leukemias
Graphical abstract
Section snippets
Flt3 and Flt3L
Protein kinases are catalysts that play a pivotal role in nearly every facet of cell biology and biochemistry [1,2]. These enzymes generate signaling modules that regulate cell cycle progression, proliferation, programmed cell death (apoptosis), cytoskeletal function, motility, differentiation, development, transcription, and translation. Owing to the numerous actions of protein kinases, it is essential that they are carefully regulated because abnormal activity can lead to cancer as well as
Primary, secondary, and tertiary structures of the Flt3 catalytic domain
The catalytic domain of Kit consists of 334 amino acid residues. The average protein kinase domain contains about 275 residues and the larger size of Flt3 is due to the inclusion of a kinase insert domain (KID) of 70 residues [19]. Based upon the amino acid sequences of about five dozen protein-tyrosine and protein-serine/threonine kinases, Hanks and Hunter partitioned protein kinases into 12 domains (I-VIA, VIB-XI) [20]. Domain I of Flt3 contains a glycine-rich loop (GRL) with a GxGxΦG
Inhibitor classification
Dar and Shokat divided protein kinase antagonists into three groups, which they labeled as types I, II, and III [56]. They classified type I inhibitors as those that bind within and around the adenine pocket of a catalytically active enzyme. Moreover, they classified type II inhibitors as those that bind to an inactive DFG-Dout protein kinase and they classified type III inhibitors as agents that bind to an allosteric site that does not overlap with the adenine-binding pocket. Subsequently,
Drug binding pockets
Liao [55] and van Linden et al. [62] divided the region between the small and large lobes of protein kinases into the front cleft (front pocket), the gate area, and the back cleft. A general overview illustrating these sites and various sub-pockets is provided in Fig. 5 and Table 3. The gate area and back cleft make up the back pocket or HPII (hydrophobic pocket II). The front cleft contains the final three residues of the β1-strand, the entire glycine-rich loop, the initial four residues of
Drug-enzyme interactions
Gilteritinib is a pyrazinecarboxamide derivative (Fig. 6A) and a Flt3 multikinase inhibitor that is US FDA approved for the treatment of adult patients with relapsed or refractory AML with a FLT3 mutation as detected by the FDA-approved LeukoStrat CDx mutation assay [67]. Besides Flt3, the drug inhibits the ALK, LTK, ROS1, and RET receptor protein-tyrosine kinases with IC50 values in the low nanomolar range [68]. The X-ray crystal structure of gilteritinib bound to Flt3 demonstrates that a
Lipinski’s rule of five (Ro5)
Medicinal chemists and pharmacologists have searched for beneficial drug-like chemical properties that result in medicines with oral therapeutic effectiveness. Lipinski’s “rule of five” is an experimental and computational methodology to estimate membrane permeability, solubility, and effectiveness in the drug-development setting [95]. It is a rule of thumb that evaluates drug-likeness and determines whether a compound with particular pharmacological activities has physical and chemical
Epilogue
Although the mode of binding or pose of each medicinal with its protein kinase target is unique, it is useful to generalize drug-enzyme interactions and employ them in the drug development and discovery process. We divided protein kinase inhibitors into seven possible types (I–VI and I½) based upon the nature of their drug-enzyme complexes [52]. The complexity of inhibitor taxonomy increases because some medications can bind to different conformations of their protein kinase targets. For
Declaration of Competing Interest
The author is unaware of any affiliations, memberships, or financial holdings that might be perceived as affecting the objectivity of this review.
Acknowledgments
The colored figures in this paper were checked to ensure that their perception was accurately conveyed to colorblind readers [111]. The author thanks Laura M. Roskoski for providing editorial and bibliographic assistance. I also thank Josie Rudnicki and Jasper Martinsek help in preparing the figures and Pasha Brezina and W.S. Sheppard for their help in structural analyses.
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2023, Pharmacological ResearchCitation Excerpt :The protein kinase spine and shell residues perform an important role in determining the structure and activity of these enzymes; one cannot overemphasize their importance in supporting the activity of this enzyme superfamily as well as their participation in their interactions with small molecule protein kinase antagonists. For an examination of the properties of the spine and shell residues and their interactions with low molecular weight inhibitors of important members of the protein kinase superfamily, see the following articles: Refs. [33–35] for the ALK pleotrophin and midkine receptor protein-tyrosine kinase, Refs. [16,36–38] for the EGFR family of protein-tyrosine kinases, Ref. [39] for the PDGFRα/β protein-tyrosine kinases, Ref. [40] for the fibroblast growth factor receptor family of protein-tyrosine kinases, Ref. [41] for the Kit stem cell receptor protein-tyrosine kinase, Ref. [42] for the RET glial-cell derived receptor protein-tyrosine kinase, Ref. [43] for the VEGFR1/2/3 protein-tyrosine kinases, Ref. [44] for the ROS1 orphan receptor protein-tyrosine kinase, Ref. [45] for the Flt3 receptor protein-tyrosine kinase, Refs. [21,46] for the BCR-Abl nonreceptor protein tyrosine kinases, Ref. [47,48] for the Janus nonreceptor protein-tyrosine kinase, Refs. [16,49] for the Bruton nonreceptor protein-tyrosine kinase, Refs. [50,51] for the Src nonreceptor protein-tyrosine kinase, Refs. [52,53] for the MEK1/2 dual specificity protein kinases, Refs. [20,54] for the cyclin-dependent protein-serine/threonine kinase family, Refs. [55,56] for the ERK1/2 protein-serine/threonine kinases, Refs. [57,58] for the RAF protein-serine/threonine kinases, and Ref. [9] for PI 3-kinase, a member of the atypical protein kinase group. The catalytic spines of protein kinases consist of two residues from the small lobe and six residues from the large lobe.