5 research outputs found
[3 + 2]-Cycloaddition reactions of allyl(cyclopentadienyl)iron(II) dicarbonyl with unactivated carbonyl compounds
Optimisation of a 5-[3-phenyl-(2-cyclic-ether)-methyl-ether]-4-aminopyrrolopyrimidine series of IGF-1R inhibitors
Taking the pyrrolopyrimidine derived IGF-1R inhibitor NVP-AEW541 as the starting point, the benzyl ether back-pocket binding moiety was replaced with a series of 2-cyclic ether methyl ethers leading to the identification of novel achiral [2.2.1]-bicyclic ether methyl ether containing analogues with improved IGF-1R activities and kinase selectivities. Further exploration of the series, including a fluorine scan of the 5-phenyl substituent, and optimisation of the sugar-pocket binding moiety identified compound 41 containing (S)-2-tetrahydrofuran methyl ether 6-fluorophenyl ether back-pocket, and cis-N-Ac-Pip sugar-pocket binding groups. Compound 41 showed improved selectivity and pharmacokinetics compared to NVP-AEW541, and produced comparable in vivo efficacy to linsitinib in inhibiting the growth of an IGF-1R dependent tumor xenograft model in the mouse
Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex
The anticancer agent indisulam inhibits cell proliferation by causing degradation of RBM39, an essential mRNA splicing factor. Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation. To delineate the precise mechanism by which indisulam mediates the DCAF15–RBM39 interaction, we solved the DCAF15–DDB1–DDA1–indisulam–RBM39(RRM2) complex structure to a resolution of 2.3 Å. DCAF15 has a distinct topology that embraces the RBM39(RRM2) domain largely via non-polar interactions, and indisulam binds between DCAF15 and RBM39(RRM2), coordinating additional interactions between the two proteins. Studies with RBM39 point mutants and indisulam analogs validated the structural model and defined the RBM39 α-helical degron motif. The degron is found only in RBM23 and RBM39, and only these proteins were detectably downregulated in indisulam-treated HCT116 cells. This work further explains how indisulam induces RBM39 degradation and defines the challenge of harnessing DCAF15 to degrade additional targets
Identification of Potent and Selective RIPK2 Inhibitors for the Treatment of Inflammatory Diseases
NOD2 (nucleotide-binding
oligomerization domain-containing protein
2) is an internal pattern recognition receptor that recognizes bacterial
peptidoglycan and stimulates host immune responses. Dysfunction of
NOD2 pathway has been associated with a number of autoinflammatory
disorders. To date, direct inhibitors of NOD2 have not been described
due to technical challenges of targeting the oligomeric protein complex.
Receptor interacting protein kinase 2 (RIPK2) is an intracellular
serine/threonine/tyrosine kinase, a key signaling partner, and an
obligate kinase for NOD2. As such, RIPK2 represents an attractive
target to probe the pathological roles of NOD2 pathway. To search
for selective RIPK2 inhibitors, we employed virtual library screening
(VLS) and structure based design that eventually led to a potent and
selective RIPK2 inhibitor <b>8</b> with excellent oral bioavailability,
which was used to evaluate the effects of inhibition of RIPK2 in various <i>in vitro</i> assays and <i>ex vivo</i> and <i>in vivo</i> pharmacodynamic models