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    Chemical Reviews pubs.acs.

    org/CR Review

    Figure 40. Binding mode of the allosteric inhibitor JBJ-04-125-02 (green) bound to the EGFR T790M and ADP complex (PDB code 6DUK).

    Figure 41. Additional approaches to target EGFR mutations.

    approved by the FDA in 1967 for ovulatory dysfunction and hyperplasia or endometrial cancer.291 Additional SERMs
    tamoxifen was approved 10 years later in 1977 for the reported include bazedoxifene, lasofoxifene, and ormeloxi-
    treatment of breast cancer (Figure 43). In breast tissue fene.290
    tamoxifen acts as an antagonist, but it acts as an agonist on Although such drugs have been incredibly valuable in the
    bone tissue; therefore, its ability to maintain bone density treatment of breast cancers for many decades, acquired
    resulted in an additional use in the treatment of osteoporosis. resistance is observed toward SERMs. Although SERMs are
    Another 20 years passed before the next-generation toremifene able to act as estrogen antagonists during successful periods of
    and raloxifene were approved in 1997 for the treatment of treatment, they can cause SERM-stimulated breast cancer
    breast cancer.290 Raloxifene also exhibits ER antagonist growths as a specific and unique mechanism of resistance.
    activity, but unlike tamoxifen the agonist activity is not Drug discovery efforts have subsequently been built on the
    observed in the uterus, with therefore a reduced risk of uttering understanding from SERMs to identify a new class of
    AF https://dx.doi.org/10.1021/acs.chemrev.0c00383
    Chem. Rev. XXXX, XXX, XXX−XXX

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