Targeted protein
degradation (TPD) holds immense promise for drug
discovery, but mechanisms of acquired resistance to degraders remain
to be fully identified. Here, we used clustered regularly interspaced
short palindromic repeats (CRISPR)-suppressor scanning to identify
mechanistic classes of drug resistance mutations to molecular glue
degraders in GSPT1 and RBM39, neosubstrates targeted by E3 ligase
substrate receptors cereblon and DCAF15, respectively. While many
mutations directly alter the ternary complex heterodimerization surface,
distal resistance sites were also identified. Several distal mutations
in RBM39 led to modest decreases in degradation, yet can enable cell
survival, underscoring how small differences in degradation can lead
to resistance. Integrative analysis of resistance sites across GSPT1
and RBM39 revealed varying levels of sequence conservation and mutational
constraint that control the emergence of different resistance mechanisms,
highlighting that many regions co-opted by TPD are nonessential. Altogether,
our study identifies common resistance mechanisms for molecular glue
degraders and outlines a general approach to survey neosubstrate requirements
necessary for effective degradation.
A new strategy for
the functionalization of sterically hindered
terminal olefins is reported. Alkenes bearing quaternary carbons at
the allylic or homoallylic position are readily oxidized to the corresponding
aldehydes by palladium/copper/nitrite catalysis. A broad range of
functional groups including esters, nitriles, silyl ethers, vinylogous
esters, ketones, lactones, and β-ketoesters are tolerated under
the reaction conditions. The crude aldehyde products can be transformed
further, enabling direct conversion of hindered terminal alkenes to
various other synthetically useful functional groups, resulting in
formal anti-Markovnikov hydroamination, among other transformations.
D 12-Prostaglandin J family is recently discovered and has potent anti-cancer activity. Concise syntheses of four D 12-prostaglandin J natural products (7-8 steps in the longest linear sequences) are reported, enabled by convergent stereoretentive cross-metathesis. Exceptional control of alkene geometry was achieved through stereoretention.
An enantioselective synthesis of 15-deoxy-Δ12,14-prostaglandin J2 is reported. The synthesis
begins with
the preparation of enantiopure 3-oxodicyclopentadiene by a lipase-mediated
kinetic resolution. A three-component coupling followed by a retro-Diels–Alder
reaction provides the C8 stereochemistry of the prostaglandin skeleton
with high enantioselectivity. Stereoretentive olefin metathesis followed
by a Pinnick oxidation affords 15-deoxy-Δ12,14-prostaglandin
J2 in high enantiopurity.
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