Cytochrome P450 enzymes can effectively
promote the activation
and cyclization of carbonazidate substrates to yield oxazolidinones
via an intramolecular nitrene C–H insertion reaction. Investigation
of the substrate scope shows that while benzylic/allylic C–H
bonds are most readily aminated by these biocatalysts, stronger, secondary
C–H bonds are also accessible to functionalization. Leveraging
this “non-native” reactivity and assisted by fingerprint-based
predictions, improved active-site variants of the bacterial P450 CYP102A1
could be identified to mediate the aminofunctionalization of two terpene
natural products with high regio- and stereoselectivity. Mechanistic
studies and KIE experiments show that the C–H activation step
in these reactions is rate-limiting and proceeds in a stepwise manner,
namely, via hydrogen atom abstraction followed by radical recombination.
This study expands the reactivity scope of P450-based catalysts in
the context of nitrene transfer transformations and provides first-time
insights into the mechanism of P450-catalyzed C–H amination
reactions.
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co‐primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/ 2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk: 0.05; HR no high-risk: 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.
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