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    • Conformational analysis provides further insight into the

    2022-01-15

    Conformational analysis provides further insight into the SAR trends apparent in . Acyclic precursors – are 25–50-fold less active than their macrocyclic counterparts – against Pyk2. The global minima for – are conformations in which the –NHCH– linker between the pyrimidine and pyridine rings is staggered, and the calculated energy penalty to adopt the gauche local minima evident in the bioactive conformation (cf c) is ca. 2.3kcal/mol. In the still more dramatic case of the tertiary amines, the 2500-fold Pyk2 potency differential is largely explained by the same phenomenon coupled with the need for the -Me substituent to lie in the same plane and pointing towards the adjacent -CF substituent – a conformation that lies 4.3kcal/mol above the global minimum for the acyclic analogue . Conformational analysis also confirms that second generation macrocycles , and can adopt a low energy conformation (either the global minimum or within 0.5kcal/mol of it) that overlays closely with the small molecule crystal structure of (). The detrimental conformational effect of -methylation is effectively overcome through macrocyclization of to . In summary, the use of a macrocyclization strategy provided an enhancement in Pyk2 vs FAK selectivity, despite the high degree of sequence similarity in their active sites. Macrocyclic atropisomerism was observed with , where the solid state conformation of was found to be remarkably similar to the Pyk2 bound conformation. The excellent potencies of macrocycles , , and (IC=0.7–3.1nM), combined with their Pyk2/FAK selectivity (2- to 3-fold), render them suitable tool compounds for future proof-of-concept studies. Improving solubility, metabolic stability and ensuring blood Icilin synthesis barrier permeability will be necessary to enable their utility in glioblastoma xenograft models. Acknowledgments
    Introduction Cancer remains a major public health problem worldwide. In 2018, 1,735,350 new cancer cases and 609,640 cancer deaths are projected to occur in the United States [1]. Small-molecule targeted therapy drugs, which are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cells, have had a significant impact on the treatment of various cancers [[2], [3], [4], [5]]. Focal adhesion kinase (FAK), a cytoplasmic protein tyrosine kinase, overexpressed and activated in several advanced-stage solid cancers [6,7]. FAK promotes tumor progression and metastasis through effects on cancer cells, as well as stromal cells of the tumor microenvironment. Targeted inhibition of the FAK pathway is a promising therapeutic approach to broadly suppress various tumor-promoting signaling pathways that converge on FAK activation [[8], [9], [10], [11]]. FAK therefore represents an important target for the development of anti-neoplastic and anti-metastatic drugs. Small-molecule FAK inhibitors are designed to bind residues that surround the ATP-binding pocket of kinases, including TAE226 (1) [12,13], PF562271(2) [14], Defactinib (3) [15], CEP-37440 (4) [16], and pyrimidines (5,6) [17,18] etc. (Fig. 1). Generally, these novel FAK inhibitors are comprised of a pyrimidine core, along with a N-methylbenzamide functional group. In cell culture and animal models, they effectively decrease FAK Y397 autophosphorylation and prevent cell migration, but do not necessarily induce cell apoptosis in adherent culture conditions [19,20]. TAE226 is a well-characterized cellular-active and selective nanomolar affinity FAK inhibitors, showing effective inhibitory activity against growth and invasion of glioma and ovarian cancer cells. In addition, TAE226 can also significantly increase the survival rate of animals with glioma Xenografts or ovarian tumor cell implants [12,13]. Recently, our efforts on structural modification of pyrimidine scaffold also led to the identification of several more potent FAK inhibitors than TAE226, such as compounds 5 and 6 [17,18]. The co-crystal structure of FAK in complex with TAE226 indicated that the hydrophilic functional group at the C-2 aniline side chain is favorable to strengthen the contacts with the amino acids Gln438 and Gly505 in the binding pocket of the FAK protein [21,22]. Our previous studies on structural modifications also revealed that H-bond, such as sulfonate and phosphate groups are favorable to increase the binding affinity with FAK kinase [17,18]. Accordingly, with the aim of producing additional kinase inhibitors with strong hydrogen-bonding affinity for FAK protein, a N-morpholine formamide functional group was introduced into the aniline side chain at the C-2 position of the pyrimidine core in this study (Fig. 2). Herein, the design strategy, synthesis and biological activity of these inhibitors in vivo and in vitro are all described in detail.