The modulation of pre‐mRNA splicing is proposed as an attractive anti‐neoplastic strategy, especially for the cancers that exhibit aberrant pre‐mRNA splicing. Here, we discovered that T‐025 functions as an orally available and potent inhibitor of Cdc2‐like kinases (CLKs), evolutionally conserved kinases that facilitate exon recognition in the splicing machinery. Treatment with T‐025 reduced CLK‐dependent phosphorylation, resulting in the induction of skipped exons, cell death, and growth suppression in vitro and in vivo. Further, through growth inhibitory characterization, we identified high CLK2 expression or MYC amplification as a sensitive‐associated biomarker of T‐025. Mechanistically, the level of CLK2 expression correlated with the magnitude of global skipped exons in response to T‐025 treatment. MYC activation, which altered pre‐mRNA splicing without the transcriptional regulation of CLKs, rendered cancer cells vulnerable to CLK inhibitors with synergistic cell death. Finally, we demonstrated in vivo anti‐tumor efficacy of T‐025 in an allograft model of spontaneous, MYC‐driven breast cancer, at well‐tolerated dosage. Collectively, our results suggest that the novel CLK inhibitor could have therapeutic benefits, especially for MYC‐driven cancer patients.

General control nonderepressible 2 (GCN2) is a master regulator kinase of amino acid homeostasis and important for cancer survival in the tumor microenvironment under amino acid depletion. We initiated studies aiming at the discovery of novel GCN2 inhibitors as first-in-class antitumor agents and conducted modification of the substructure of sulfonamide derivatives with expected type I half binding on GCN2. Our synthetic strategy mainly corresponding to the αC-helix allosteric pocket of GCN2 led to significant enhancement in potency and a good pharmacokinetic profile in mice. In addition, compound 6d, which showed slow dissociation in binding on GCN2, demonstrated antiproliferative activity in combination with the asparagine-depleting agent asparaginase in an acute lymphoblastic leukemia (ALL) cell line, and it also displayed suppression of GCN2 pathway activation with asparaginase treatment in the ALL cell line and mouse xenograft model.

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This account describes coupling reaction of 1,3-disubstituted secondary allylic carbonates with lithium aryl-and alkenylborates in the presence of a nickel catalyst. Borates examined are 4, 5, and 6, and reactivity and selectivity were investigated using the allylic carbonates 1a and 1b. Coupling of 1a,b with borates 4 was effected with the nickel catalyst, NiCl 2 (PPh 3 ) 2 or NiCl 2 (dppf), in THF at 45-65°C to provide products 3 in good yields with almost 100% regio-and stereoselectivities. Trivalent organoboranes prepared from acetylenes by hydroboration with catecholborane also underwent coupling reaction with 1a,b after transformation to borates 5 with MeLi. Though coupling using 4 and 5 required elevated temperature (45-65°C), cyclic borates 6 prepared in situ from boronates 8 and MeLi were found to couple with 1a,b at room temperature or below. Regio-and stereoselectivities were almost 100% as were observed in the cases of 4 and 5. In these reactions, palladium complexes such as Pd(PPh 3 ) 4 , Pd 2 (dba) 3 ‚CHCl 3 + 2 PPh 3 showed no catalytic activity. Stereochemical aspect of the present reaction was studied using cyclohexenyl carbonate 24 with 2-furylborate 4e and phenylborate 6a, and was found to proceed with overall anti fashion. With additional experiments, the mechanism of the present reaction was discussed in terms of transient π-allylnickel intermediates.

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(Trimethylsilyl)ethylene-titanium alkoxide complex (1) was generated from trimethyl(vinyl)silane, Ti(O-i-Pr)(4), and i-PrMgCl as a preformed alkene-titanium complex and reacted with several unsaturated compounds such as aldehyde, imine, other vinylsilane, and acetylene to give the corresponding coupling products 4a-f, 6, 8, and 10a-d in a regioselective manner. Both of the two carbon-titanium bonds of the complex 1 reacted successively with esters to afford silylcyclopropanols 11a-j, 13, and 15, some synthetic applications of which were illustrated in the preparation of beta-silyl ketones 16 and cyclopropenes 17. Asymmetric addition of 1 to a chiral acyloxazolidinone 19 gave optically active cyclopropanol (+)-11a of 50% ee.

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