Chemical Reviews pubs.acs.
org/CR Review
NSCLC. It has been observed, however, that “type II” which are able to target the CNS and achieve brain
inhibitors such as cabozantinib are able to overcome this penetration. Key to achieving such a profile appears to be
mutation and maintain target activity.224 maintaining high intrinsic permeability while minimizing
4.3. Change Drug Mechanism of Action compound efflux as discussed in section 2.1.52 A range of
preclinical models is available to guide the evolution of
One of the most notable examples of a change in the chemical series toward improved brain penetration. Examples
mechanism of a compound to overcome a resistance of later generation drugs with improved blood−brain barrier
mechanism is for the kinase EGFR in the treatment of permeability, which may enable the improved treatment of
NSCLC. Although first-generation inhibitors such as gefitinib patients with brain metastasis, or avoid the appearance of brain
and erlotinib were effective and showed high response rates, metastasis, include the ALK inhibitor lorlatinib129 and the
resistance emerged often within 9−12 months due to the EGFR mutant inhibitors AZD3759376 and osimertinib.377
T790M gatekeeper mutation.22 Initially assumed to be a steric
4.6. Combination Studies
effect similar to BCR/ABL, it was subsequently shown that the
primary effect of this mutation was the increase of the affinity In response to the emerging challenges around cancer drug
of ATP which rendered all reversible ATP pocket inhibitors resistance, the use of drug combinations has become a highly
significantly less active.80 Subsequently, irreversible covalent important area in which progress is currently being made.378
inhibitors were discovered based on different chemical This approach is not without challenge as there are a vast
templates to target the mutations specifically and have a number of possible combination studies that could be
selectivity margin to the wild-type form of the protein. The evaluated in a clinical setting; therefore, understanding the
first approved inhibitor with such a profile was osimertinib.238 optimal combinations informed by preclinical studies is
PROTACs are being developed to target a number of essential. The aim of such drug combinations could be
clinically relevant targets where resistance has emerged (Figure synergistic or additive combinations, synthetic lethality, or the
55).373 One rationale here is that degrading the target may reversal of resistance through additional targeting of alternative
delay or avoid the emergence of the resistance mutations pathways/mutations. To help enable this, there are a number
arising from more traditional small molecule inhibitors.264 of preclinical methods, both experimental379 and computa-
Compounds have been disclosed targeting EGFR (based on tional,380 that can be utilized to identify rationale drug
ATP competitive265,266 and allosteric molecules267), BTK,185 combination treatments for evaluating in a clinical trial.
and BRC/ABL164 with this mechanism of action aimed at
targeting various resistance forms. Interestingly, such an 5. FINAL REMARKS
approach may be vulnerable to specific resistance mechanisms
The previously highlighted WHO Report on Cancer from
either from compound binding to the primary target or via the
2020 discusses additional challenges beyond the scientific ones,
ability of the compound to recruit the E3 ligase. In a recent
with a target to save 7.3 million lives by 2030.1 Important
publication evaluating BET family targeted PROTACs, drug
aspects of this report are around increasing the uptake of
induced resistance was observed not from mutations which
preventative measures, improving early cancer detection in
impact the ability for the compounds to bind to BRD4 but via
patients, and enabling wider patient access worldwide to the
genomic alterations that impact core components of the E3
most effective cancer treatments.
ligase complex.374
Significant progress has been made in the past few decades
4.4. Target Alternative Binding Site in the targeted treatment of a range of oncology indications.
An additional approach to avoid the impact of specific This has been enabled and driven by an increased under-
mechanisms of resistance to one binding site can be to target standing of the fundamental mechanisms driving these cancers.
an alternative pocket of the drug target. Binding distal from However, drug resistance is an ongoing challenge in the
such mutations would be expected to maintain target activity discovery of novel cancer drugs which have the potential to
assuming there is no long-range impact or communication positively impact the lives of patients. One of the most
between the different sites. A specific example of this approach interesting currently emerging stories of innate and acquired
comes from BCR/ABL, where researchers identified a novel resistance is for drug molecules targeting the mutant G12C
scaffold which did not bind to the ATP pocket where imatinib form of the oncogene RAS.381 Previously considered largely
binds. This approach resulted in the discovery of asciminib, intractable to small molecule inhibition, a novel disulfide
targeting the myristate pocket.160 The identification of covalent approach enabled the discovery of covalent inhibitors
allosteric inhibitors provides options not only to sequence against the target.382 Covalent small molecule inhibitors such
drug treatments when one fails, but also a “double hit” strategy as AMG 510383 and MRTX849384 have recently entered phase
where two compounds are tested in combination with the aim I trials and encouraging clinical responses have been reported;
of avoiding additional resistance mutations.262 however, we have yet to fully understand the potential for
innate and or acquired resistance in the various disease settings
4.5. Improvement in Blood−Brain Barrier Permeability with these agents. It will be interesting to understand how such
(BBBP) mechanisms may mirror experiences with other covalent
One of the more generic resistance mechanisms to targeted agents. In a further sign of progress, additional approaches
cancer drugs can be the appearance of brain metastasis as an are being disclosed to target additional RAS mutants and via
escape mechanism in response to drugs which are unable to SOS1, which activates RAS.385
penetrate the blood−brain barrier.375 This has been observed A recent review from Vasan et al.386 summarized the
in not only broader agents such as chemotherapies but also challenge of cancer resistance as multifaceted. The suggested
more targeted agents.51 As with the emergence of resistance “key determinants” of cancer resistance included tumor burden
from amino acid mutations, understanding these cases has and growth kinetics, tumor heterogeneity, the physical barriers
enabled drug discovery scientists to develop additional agents of the cell membrane, the immune system and microenviron-
AP https://dx.doi.org/10.1021/acs.chemrev.0c00383
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