Accumulating evidence indicates that p53 is the most frequently mutated gene in human cancers, with mutations in over 50% of human cancers [
8]. The majority of p53 mutations are missense mutations in the DNA-binding domain. Mutations in p53 result in the loss of function (LOS) as a transcription factor and a tumor suppressor. However, missense mutp53 frequently accumulates in tumors to promote malignant progression, metastasis, and drug resistance in a manner independent of wtp53. These oncogenic mutp53 activities are referred to as gain of function (GOF) (
Figure 1). The mechanism of mutp53 GOF is mainly caused by mutp53’s ability to bind to tumor suppressors (e.g., p63, p73, MRN complex) and oncogenes (e.g., ETS2, SREBP2, NF-Y) to alter the functions of these binding partners [
2,
3,
9]. Clinically, the presence of mutp53 in tumors is well correlated with advanced clinical stages, metastases, and poor outcomes in patients with multiple types of cancer [
10,
11]. Given that mutations in p53 are generally observed specifically in tumors and are rare in non-tumor tissues, mutp53 is an ideal therapeutic target for cancer therapy.
Several strategies to target p53 mutations have been taken (
Figure 1). The first strategy is to directly target missense mutp53 to restore the activity of wtp53 or stabilize the wtp53 conformation. Drugs or compounds that have this function are referred to as reactivators. The most representative drug in this group is APR-246 (eprenetapopt/PRIMA-1MET), which is in several phase 2 or 3 clinical trials.
Although the tumor suppressive effects of APR-246 in mutp53-carrying tumors in mouse models have been shown to be successful, it is not yet approved by the Food and Drug Administration (FDA) [
12]. The second strategy is to induce degradation or depletion of missense mutp53, which capitalizes upon the addiction of cancer cells to mutp53 and potentially restores the activities of some tumor suppressors, including p63 and p73, whose functions have been suppressed by mutp53.
Drugs or compounds employed for this strategy include HSP90 inhibitors or statins, cholesterol-lowering drugs that are shown to induce degradation of mutp53, leading to tumor suppression [
13,
14]. The third strategy is to induce cell death specifically in cancer cells with p53 deletions or mutations, so called p53 synthetic lethality [
15]. This strategy often targets vulnerabilities imposed by p53 deficiency or mutp53 GOF, instead of directly targeting mutp53. Drugs or compounds used for this strategy include Wee1 inhibitors or inhibitors of DNA damage response signaling (e.g., ATR or Chk1/2 inhibitors) [
16,
17,
18]. Other strategies include wtp53 rescue of non-sense mutations in p53 [
19,
20], inhibition of retrotransposon activated upon p53 deficiency [
19], and inhibition of YAP/TAZ function activated by mutp53 [
21,
22]. Here, we have summarized updated information about drugs developed for the aforementioned strategies that are approved by the FDA or are in clinical trials, including their mechanisms of action and activities to suppress cancer progression (
Table 1).