DNA polymerase theta (Polθ)
is an attractive synthetic lethal
target for drug discovery, predicted to be efficacious against breast
and ovarian cancers harboring BRCA-mutant alleles. Here, we describe
our hit-to-lead efforts in search of a selective inhibitor of human
Polθ (encoded by POLQ). A high-throughput screening campaign
of 350,000 compounds identified an 11 micromolar hit, giving rise
to the N2-substituted fused pyrazolo series, which was validated by
biophysical methods. Structure-based drug design efforts along with
optimization of cellular potency and ADME ultimately led to the identification
of RP-6685: a potent, selective, and orally bioavailable
Polθ inhibitor that showed in vivo efficacy in an HCT116 BRCA2–/– mouse tumor xenograft model.
Nucleoside analogues bearing a fluorine in the C2'-position have been synthesized by S2-like cyclizations of acyclic thioaminal precursors. This strategy provides access to two scaffolds, d-1',2'-cis-thiofuranosides and d-1',2'-trans-furanosides, which are difficult to generate using the standard approach for nucleoside synthesis. The addition of silylated nucleobases onto model C2-fluorinated dithioacetal substrates resulted in 1,2-syn diastereoselectivity, which is consistent with the C2-F and S-alkyl moiety being in close proximity. A new series of analogues bearing a C3' all-carbon quaternary center along with a C2'-F atom have also been synthesized using this approach and are being investigated as potential antimetabolites.
Radical reductions of halogenated precursors bearing a heterocycle exo (α) to the carbon-centered radical proceed with enhanced anti-selectivity, a phenomenon that we termed "exocyclic effect". New experimental data and DFT calculations at the BHandHLYP/TZVP level demonstrate that the origin of the exocyclic effect is linked to the strain energy required for a radical intermediate to reach its reactive conformation at the transition state (ΔE(≠)(strain)). Furthermore, radical reductions of constrained THP systems indicate that high 2,3-anti inductions are reached only when the radical chain occupies an equatorial orientation. Hydride deliveries to different acyclic substrates and calculations also suggest that the higher anti-selectivities obtained with borinate intermediates are not related to the formation of a complex mimicking an exocycle. From a broader standpoint, this study reveals important conformational factors for reactions taking place at a center vicinal to a heterocycle or an α-alkoxy group.
The design of a novel nucleoside scaffold that exhibits an all-carbon quaternary center is reported. This allows for both α- and β-anomers of a given 2'-deoxy-2',2'-difluoro nucleoside analog (NA) to have potential biological activity. Using an intramolecular atom-transfer reaction, an all-carbon quaternary center was obtained without the use of heavy metals and/or harsh conditions. The chemistry developed is efficient, easily scalable and leads to novel libraries of molecules.
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