Chemical Reviews pubs.acs.
org/CR Review
Figure 50. Selected published MEK1/2 and ERK1/2 inhibitors. Trametinib (MEK1/2) and the ERK1/2 inhibitors SCH900353, ulixertinib/BVD-
523, GDC-0994, LY-3214996, CC-90003, and AZD0364.
approval in 2018 (Figure 51). Niraparib was approved in 2017 broad classes of observed resistance, such as inhibitor/drug
for the treatment of ovarian, fallopian tube, and primary efflux, the loss of PARP or a binding site mutation, changes in
peritoneal cancers, and talazoparib was approved in 2018 for PAR metabolism, restoration of HR, or rewiring of replication
breast cancer. fork protection. In terms of addressing such mechanisms of
Although these compounds can demonstrate strong initial resistance, combination approaches are being evaluated to
responses in the right clinical setting, disease progression is
include ATR, WEE1, CHK1, and immuno-oncology (IO) and
often observed. One example of this is resistance by
approximately one-third of patients within 36 months with checkpoint agents. As a result of this complexity, it may be
first-line olaparib treatment in BRCA1/2 mutant ovarian expected that the clinical mechanisms of resistance will be
cancer. For this reason a range of in vitro and in vivo more diverse and dependent on the specific disease setting, but
approaches has been deployed to evaluate potential clinical such emerging information may identify additional drug
mechanisms of resistance.351 These studies have identified five discovery strategies to combat clinical needs.
AL https://dx.doi.org/10.1021/acs.chemrev.0c00383
Chem. Rev. XXXX, XXX, XXX−XXX
