Design of small-molecule inhibitors (MDM2 inhibitors) to block the MDM2-p53 protein-protein interaction has been pursued as a new cancer therapeutic strategy. In recent years, potent, selective, and ...efficacious MDM2 inhibitors have been successfully obtained and seven such compounds have been advanced into early phase clinical trials for the treatment of human cancers. Here, we review the design, synthesis, properties, preclinical, and clinical studies of these clinical-stage MDM2 inhibitors.
Tumor suppressor p53 is an attractive cancer therapeutic target because it can be functionally activated to eradicate tumors. Direct gene alterations in p53 or interaction between p53 and MDM2 ...proteins are two alternative mechanisms for the inactivation of p53 function. Designing small molecules to block the MDM2-p53 interaction and reactivate the p53 function is a promising therapeutic strategy for the treatment of cancers retaining wild-type p53. This review will highlight recent advances in the design and development of small-molecule inhibitors of the MDM2-p53 interaction as new cancer therapies. A number of these small-molecule inhibitors, such as analogs of MI-219 and Nutlin-3, have progressed to advanced preclinical development or early phase clinical trials.
The past decade has witnessed tremendous advances in the discovery and development of novel small-molecule inhibitors targeting apoptosis pathways for cancer treatment, with some compounds now in ...clinical development. Early promising clinical data have been reported with these new classes of anticancer drugs. This review highlights the recent advancements in the development of small-molecule inhibitors targeting three major classes of antiapoptotic proteins: antiapoptotic B cell lymphoma 2 (BCL-2) proteins, inhibitor of apoptosis proteins (IAPs), and murine double-minute 2 (MDM2). Special emphasis is given to those that have been advanced into clinical trials. The challenges and future directions in the further preclinical and clinical development of these new anticancer drugs are also discussed.
Src homology 2 domain-containing phosphatase 2 (SHP2) is an attractive therapeutic target for human cancers and other human diseases. Herein, we report our discovery of potent small-molecule SHP2 ...degraders whose design is based upon the proteolysis-targeting chimera (PROTAC) concept. This work has led to the discovery of potent and effective SHP2 degraders, exemplified by SHP2-D26. SHP2-D26 achieves DC50 values of 6.0 and 2.6 nM in esophageal cancer KYSE520 and acute myeloid leukemia MV4;11 cells, respectively, and is capable of reducing SHP2 protein levels by >95% in cancer cells. SHP2-D26 is >30-times more potent in inhibition of phosphorylation of extracellular signal-regulated kinase (ERK) and of cell growth than SHP099, a potent SHP2 inhibitor, in KYSE520 and MV4;11 cancer cell lines. This study demonstrates that induced SHP2 degradation is a very effective approach to inhibit the function of SHP2. Further optimization of these SHP2 degraders may lead to the development of a new class of therapies for cancers and other human diseases.
p53 is a powerful tumor suppressor and is an attractive cancer therapeutic target because it can be functionally activated
to eradicate tumors. The gene encoding p53 protein is mutated or deleted in ...half of human cancers, which inactivates its tumor
suppressor activity. In the remaining cancers with wild-type p53 status, its function is effectively inhibited through direct
interaction with the human murine double minute 2 (MDM2) oncoprotein. Blocking the MDM2-p53 interaction to reactivate the
p53 function is a promising cancer therapeutic strategy. This review will highlight the advances in the design and development
of small-molecule inhibitors of the MDM2-p53 interaction as a cancer therapeutic approach.
We report herein the discovery of highly potent PROTAC degraders of androgen receptor (AR), as exemplified by compound 34 (ARD-69). ARD-69 induces degradation of AR protein in AR-positive prostate ...cancer cell lines in a dose- and time-dependent manner. ARD-69 achieves DC50 values of 0.86, 0.76, and 10.4 nM in LNCaP, VCaP, and 22Rv1 AR+ prostate cancer cell lines, respectively. ARD-69 is capable of reducing the AR protein level by >95% in these prostate cancer cell lines and effectively suppressing AR-regulated gene expression. ARD-69 potently inhibits cell growth in these AR-positive prostate cancer cell lines and is >100 times more potent than AR antagonists. A single dose of ARD-69 effectively reduces the level of AR protein in xenograft tumor tissue in mice. Further optimization of ARD-69 may ultimately lead to a new therapy for AR+, castration-resistant prostate cancer.
The androgen receptor (AR) has been found to be expressed in the majority of human breast cancer and AR antagonists, such as enzalutamide, have shown promising clinical activity in AR-positive (AR+) ...breast cancer. We have recently reported the discovery of a highly potent PROTAC AR degrader, ARD-61. In this study, we evaluated ARD-61 for its therapeutic potential and mechanism of action in breast cancer models in vitro and in vivo. ARD-61 potently and effectively induces AR degradation in AR+ breast cancer cell lines and is much more potent than enzalutamide in inhibition of cell growth and induction of cell cycle arrest and/or apoptosis. ARD-61 effectively induces complete AR degradation in xenograft tumor tissue and is more effective than enzalutamide in achieving tumor growth inhibition in the MDA-MB-453 xenograft model in mice. Our study provides strong preclinical rationale to develop AR degraders for the treatment of AR+ human breast cancer.
Human murine double minute 2 (MDM2) protein is a primary endogenous cellular inhibitor of the tumor suppressor p53 and has been pursued as an attractive cancer therapeutic target. Several potent, ...nonpeptide, small-molecule inhibitors of MDM2 are currently in clinical development. In this paper, we report our design, synthesis, and evaluation of small-molecule MDM2 degraders based on the proteolysis targeting chimera (PROTAC) concept. The most promising compound (MD-224) effectively induces rapid degradation of MDM2 at concentrations <1 nM in human leukemia cells. It achieves an IC50 value of 1.5 nM in inhibition of growth of RS4;11 cells and also low nanomolar IC50 values in a panel of leukemia cell lines. MD-224 achieves complete and durable tumor regression in vivo in the RS4;11 xenograft tumor model in mice at well-tolerated dose schedules. MD-224 is thus a highly potent and efficacious MDM2 degrader and warrants extensive evaluations as a new class of anticancer agent.
Abstract Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non–small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been ...found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro . Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines. Rather, overexpression of phospho-ALK and alternative receptor tyrosine kinases such as phospho-EGFR, phospho-HER3, and phospho-IGFR-1R was observed in both resistant cell lines. Additionally, NRG1, a ligand for HER3, is upregulated and responsible for resistance by activating the EGFR family pathways through the NRG1-HER3-EGFR axis. Combination treatment with EGFR inhibitors, in particular afatinib, was shown to be effective at overcoming resistance. Our study provides new mechanistic insights into adaptive resistance to second-generation ALK inhibitors and suggests a potential clinical strategy to combat resistance to these second-generation ALK inhibitors in NSCLC.
Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. Progression to CRPC after androgen ablation therapy is predominantly driven by deregulated ...androgen receptor (AR) signalling. Despite the success of recently approved therapies targeting AR signalling, such as abiraterone and second-generation anti-androgens including MDV3100 (also known as enzalutamide), durable responses are limited, presumably owing to acquired resistance. Recently, JQ1 and I-BET762 two selective small-molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit anti-proliferative effects in a range of malignancies. Here we show that AR-signalling-competent human CRPC cell lines are preferentially sensitive to bromodomain and extraterminal (BET) inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ1 (refs 11, 13). Like the direct AR antagonist MDV3100, JQ1 disrupted AR recruitment to target gene loci. By contrast with MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR-mediated gene transcription, including induction of the TMPRSS2-ERG gene fusion and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft mouse models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer.
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