Expression of the cell cycle regulatory gene CDK6 is required for Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) cell growth, whereas expression of the closely related CDK4 protein is dispensable. Moreover, CDK6 silencing is more effective than treatment with the dual CDK4/6 inhibitor palbociclib in suppressing Ph+ ALL in mice, suggesting that the growth-promoting effects of CDK6 are, in part, kinase-independent in Ph+ ALL. Accordingly, we developed CDK4/6–targeted proteolysis-targeting chimeras (PROTACs) that inhibit CDK6 enzymatic activity in vitro, promote the rapid and preferential degradation of CDK6 over CDK4 in Ph+ ALL cells, and markedly suppress S-phase cells concomitant with inhibition of CDK6-regulated phospho-RB and FOXM1 expression. No such effects were observed in CD34+ normal hematopoietic progenitors, although CDK6 was efficiently degraded. Treatment with the CDK6-degrading PROTAC YX-2-107 markedly suppressed leukemia burden in mice injected with de novo or tyrosine kinase inhibitor–resistant primary Ph+ ALL cells, and this effect was comparable or superior to that of the CDK4/6 enzymatic inhibitor palbociclib. These studies provide “proof of principle” that targeting CDK6 with PROTACs that inhibit its enzymatic activity and promote its degradation represents an effective strategy to exploit the “CDK6 dependence” of Ph+ ALL and, perhaps, of other hematologic malignancies. Moreover, they suggest that treatment of Ph+ ALL with CDK6-selective PROTACs would spare a high proportion of normal hematopoietic progenitors, preventing the neutropenia induced by treatment with dual CDK4/6 inhibitors.
Inhibition of histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic strategy for the treatment of cancer, chemotherapy-induced peripheral neuropathy, and neurodegenerative disease. The recent X-ray crystal structure determination of HDAC6 enables an understanding of structural features directing affinity and selectivity in the active site. Here, we present the X-ray crystal structures of five HDAC6-inhibitor complexes that illuminate key molecular features of inhibitor linker and capping groups that facilitate and differentiate binding to HDAC6. In particular, aromatic and heteroaromatic linkers nestle within an aromatic cleft defined by F583 and F643, and different aromatic linkers direct the capping group toward shallow pockets defined by the L1 loop, the L2 loop, or somewhere in between these pockets. These results expand our understanding of factors contributing to the selective inhibition of HDAC6, particularly regarding interactions that can be targeted in the region of the L2 pocket.
In light of their occurrence in a broad spectrum of natural alkaloids and several important pharmaceutically active compounds, [1] such as those outlined in Scheme 1, enantioenriched indolines have triggered increasing attention in both the synthetic and medicinal chemistry communities. [2] While a variety of protocols, including traditional enzymatic or non-enzymatic kinetic resolutions, [3] and organicmolecule-or metal-mediated asymmetric transformations [4] have been described, the direct asymmetric reduction of prochiral indole precursors would be one of the most straightforward ways to make chiral indolines.[5] Thus, a few transition metal/chiral phosphine complexes, including Rh, Ru, and Ir, have been applied by the groups of Kuwano, Feringa, Pfaltz, and others to the asymmetric hydrogenation of indoles, but the methods usually suffer from a limited substrate scope and relatively harsh reaction conditions.[6] A noteworthy breakthrough was made by Zhou, Zhang, and coworkers who reported an elegant palladium-catalyzed enantioselective hydrogenation of unprotected indoles activated by Brønsted acids. [7] In contrast, Rueping et al. presented the chiral Brønsted acid catalyzed transfer hydrogenation of 3H-indoles with Hantzsch dihydropyridine as the hydrogen source.[8] Nevertheless, to the best of our knowledge, there is no successful precedent on the direct asymmetric reduction of 1H-indoles to access chiral indolines under metal-free conditions despite the fantastic progress of organocatalysis over the past decade.[9]Recently we discovered a highly diastereoselective intramolecular direct imino-ene reaction of indoles tethered to an olefinic side chain at C3, in which a Lewis acid promoted enamine-imine isomerization of the indole through C3 protonation was key to its success.[10] We also recognized that, for unprotected indoles, a similar C3 protonation would occur in the presence of suitable Brønsted acids, which would destroy the aromaticity of indoles and result in the formation of electrophilic indolenium ions.[11] We envisioned that the asymmetric reduction of indoles might be realized by utilizing a chiral organocatalytic system that is compatible with a Brønsted acid activation process. Herein we report our endeavors on the first direct enantioselective hydrosilylation of prochiral 1H-indoles by combined Brønsted acid/Lewis base activation (Scheme 2). [12] The initial investigation in the direct hydrosilylation of 2-methylindole (2 a) with excess HSiCl 3 was conducted by employing N,N-dimethylformamide (1 a; DMF) as the Lewis base catalyst at 0 8C. One equivalent of H 2 O was added to react with HSiCl 3 to generate a strong Brønsted acid, HCl. [13] The reaction was quite inspiring, and the desired indoline product 3 a was cleanly obtained in high yield after 24 hours Scheme 1. Representative chiral indoline derivatives.Scheme 2. Proposed direct asymmetric hydrosilylation of indoles through both Lewis base and Brønsted acid activations.
The dopamine transporter (DAT) serves a pivotal role in controlling dopamine (DA)-mediated neurotransmission by clearing DA from synaptic and perisynaptic spaces and controlling its action at postsynaptic DA receptors. Major drugs of abuse such as amphetamine and cocaine interact with DAT to mediate their effects by enhancing extracellular DA concentrations. We previously identified a novel allosteric site in the related human serotonin transporter that lies outside the central substrate and inhibitor binding pocket. We used the hybrid structure based (HSB) method to screen for allosteric modulator molecules that target a similar site in DAT. We identified a compound, KM822, that was found to be a selective, noncompetitive inhibitor of DAT. We confirmed the structural determinants of KM822 allosteric binding within the allosteric site by structure/function and substituted cysteine scanning accessibility biotinylation experiments. In the in vitro cell-based assay and ex vivo in both rat striatal synaptosomal and slice preparations, KM822 was found to decrease the affinity of cocaine for DAT. The in vivo effects of KM822 on cocaine were tested on psychostimulant-associated behaviors in a planarian model where KM822 specifically inhibited the locomotion elicited by DAT-interacting stimulants amphetamine and cocaine. Overall, KM822 provides a unique opportunity as a molecular probe to examine allosteric modulation of DAT function.
The first chemo- and alpha-regioselective asymmetric Michael addition of gamma,gamma-disubstituted alpha,beta-unsaturated aldehydes to nitroolefins has been presented in excellent diastereo- and enantioselectivities (dr up to >99:1, 93-96% ee) via dienamine catalysis. The Michael adducts have been efficiently converted to a number of optically pure cyclic frameworks with versatile scaffold diversity.
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