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Background Bone is the most common site of metastasis of prostate cancer (PCa). PCa invasion leads to a disruption of osteogenic-osteolytic balance and causes abnormal bone formation. The interaction between PCa and bone stromal cells, especially osteoblasts (OB), is considered essential for the disease progression. However, drugs that effectively block the cancer-bone interaction and regulate the osteogenic-osteolytic balance remain undiscovered. Methods A reporter gene system was constructed to screen compounds that could inhibit PCa-induced OB activation from 631 compounds. Then, the pharmacological effects of a candidate drug, Procoxacin (Pro), on OBs, osteoclasts (OCs) and cancer-bone interaction were studied in cellular models. Intratibial inoculation, micro-CT and histological analysis were used to explore the effect of Pro on osteogenic and osteolytic metastatic lesions. Bioinformatic analysis and experiments including qPCR, western blotting and ELISA assay were used to identify the effector molecules of Pro in the cancer-bone microenvironment. Virtual screening, molecular docking, surface plasmon resonance assay and RNA knockdown were utilized to identify the drug target of Pro. Experiments including co-IP, western blotting and immunofluorescence were performed to reveal the role of Pro binding to its target. Intracardiac inoculation metastasis model and survival analysis were used to investigate the therapeutic effect of Pro on metastatic cancer. Results Luciferase reporter gene consisted of Runx2 binding sequence, OSE2, and Alp promotor could sensitively reflect the intensity of PCa-OB interaction. Pro best matched the screening criteria among 631 compounds in drug screening. Further study demonstrated that Pro effectively inhibited the PCa-induced osteoblastic changes without killing OBs or PCa cells and directly killed OCs or suppressed osteoclastic functions at very low concentrations. Mechanism study revealed that Pro broke the feedback loop of TGF-β/C-Raf/MAPK pathway by sandwiching into 14–3-3ζ/C-Raf complex and prevented its disassociation. Pro treatment alleviated both osteogenic and osteolytic lesions in PCa-involved bones and reduced the number of metastases of PCa in vivo. Conclusions In summary, our study provides a drug screening strategy based on the cancer-host microenvironment and demonstrates that Pro effectively inhibits both osteoblastic and osteoclastic lesions in PCa-involved bones, which makes it a promising therapeutic agent for PCa bone metastasis. Graphical Abstract

Development of proteolysis targeting chimeras (PROTACs) is emerging as a promising strategy for targeted protein degradation. However, the drug development using the heterobifunctional PROTAC molecules is generally limited by poor membrane permeability, low in vivo efficacy and indiscriminate distribution. Herein an aptamer-PROTAC conjugation approach was developed as a novel strategy to improve the tumor-specific targeting ability and in vivo antitumor potency of conventional PROTACs. As proof of concept, the first aptamer-PROTAC conjugate (APC) was designed by conjugating a BET-targeting PROTAC to the nucleic acid aptamer AS1411 (AS) via a cleavable linker. Compared with the unmodified BET PROTAC, the designed molecule (APR) showed improved tumor targeting ability in a MCF-7 xenograft model, leading to enhanced in vivo BET degradation and antitumor potency and decreased toxicity. Thus, the APC strategy may pave the way for the design of tumor-specific targeting PROTACs and have broad applications in the development of PROTAC-based drugs.

The dose-related adverse effects of MDM2‒P53 inhibitors have caused significant concern in the development of clinical safe anticancer agents. Herein we report an unprecedented homo-PROTAC strategy for more effective disruption of MDM2‒P53 interaction. The design concept is inspired by the capacity of sub-stoichiometric catalytic PROTACs enabling to degrade an unwanted protein and the dual functions of MDM2 as an E3 ubiquitin ligase and a binding protein with tumor suppressor P53. The new homo-PROTACs are designed to induce self-degradation of MDM2. The results of the investigation have shown that PROTAC 11a efficiently dimerizes MDM2 with highly competitive binding activity and induces proteasome-dependent self-degradation of MDM2 in A549 non-small cell lung cancer cells. Furthermore, markedly, enantiomer 11a-1 exhibits potent in vivo antitumor activity in A549 xenograft nude mouse model, which is the first example of homo-PROTAC with in vivo therapeutic potency. This study demonstrates the potential of the homo-PROTAC as an alternative chemical tool for tumorigenic MDM2 knockdown, which could be developed into a safe therapy for cancer treatment., Graphical abstract “Suicide” cleavage of MDM2: a homo-PROTAC strategy possessing effective in vitro and in vivo antitumor activities is demonstrated for the first time. The approach may offer an opportunity to overcome the bottleneck of the dose-related adverse effects of MDM2‒P53 inhibitors in the development of clinical anticancer agents.Image 1

As one of the most aggressive and lethal human malignancies with extremely poor prognosis, there is an urgent demand of more effective therapy for the treatment of pancreatic cancer. Reported here is a new, effective therapeutic strategy and the design of small-molecule inhibitors that simultaneously target bromodomain and extra-terminal (BET) and histone deacetylase (HDAC), potentially serving as promising therapeutic agents for pancreatic cancer. A highly potent dual inhibitor (13 a) is identified to possess excellent and balanced activities against BRD4 BD1 (IC50 =11 nm) and HDAC1 (IC50 =21 nm). Notably, this compound shows higher in vitro and in vivo antitumor potency than the BET inhibitor (+)-JQ1 and the HDAC inhibitor vorinostat, either alone or and in combination, highlighting the advantages of BET/HDAC dual inhibitors for more effective treatment of pancreatic cancer.

Bromodomain-containing protein 4 (BRD4) has emerged as a promising treatment target for bone-related disorders. (+)-JQ1, a thienotriazolodiazepine compound, has been shown to inhibit pro-osteoclastic activity in a BRD4-dependent approach and impede bone loss caused by ovariectomy (OVX) in vivo. However, clinical trials of (+)-JQ1 are limited because of its poor druggability. In this study, we synthesized a new (+)-JQ1 derivative differing in structure and chirality. One such derivative, (+)-ND, exhibited higher solubility and excellent inhibitory activity against BRD4 compared with its analogue (+)-JQ1. Interestingly, (-)-JQ1 and (-)-ND exhibited low anti-proliferative activity and had no significant inhibitory effect on RANKL-induced osteoclastogenesis as compared with (+)-JQ1 and (+)-ND, suggesting the importance of chirality in the biological activity of compounds. Among these compounds, (+)-ND displayed the most prominent inhibitory effect on RANKL-induced osteoclastogenesis. Moreover, (+)-ND could inhibit osteoclast-specific gene expression, F‐actin ring generation, and bone resorption in vitro and prevent bone loss in OVX mice. Collectively, these findings indicated that (+)-ND represses RANKL‐stimulated osteoclastogenesis and averts OVX-triggered osteoporosis by suppressing MAPK and NF-κB signalling cascades, suggesting that it may be a prospective candidate for osteoporosis treatment.

p53-Murine double minute 2 (MDM2) interaction and histone deacetylases (HDACs) are important targets in antitumor drug development. Inspired by the synergistic effects between MDM2 and HDACs, the first MDM2/HDACs dual inhibitors were identified, which showed excellent activities against both targets. In particular, compound 14d was proven to be a potent and orally active MDM2/HDAC dual inhibitor, whose antitumor mechanisms were validated in cancer cells. Compound 14d showed excellent in vivo antitumor potency in the A549 xenograft model, providing a promising lead compound for the development of novel antitumor agents. Also, this proof-of-concept study offers a novel and efficient strategy for multitargeting antitumor drug discovery.

[Image: see text] In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, the first generation of dual indoleamine 2,3-dioxygenase 1 (IDO1) and histone deacetylase (HDAC) inhibitors were designed. The highly active dual inhibitor 10 showed excellent and balanced activity against both IDO1 (IC(50) = 69.0 nM) and HDAC1 (IC(50) = 66.5 nM), whose dual targeting mechanisms were validated in cancer cells. Compound 10 had good pharmacokinetic profiles as an orally active antitumor agent and significantly reduced the l-kynurenine level in plasma. In particular, it showed excellent in vivo antitumor efficacy in the murine LLC tumor model with low toxicity. This proof-of-concept study provided a novel strategy for cancer treatment. Compound 10 represents a promising lead compound for the development of novel antitumor agents and can also be used as a valuable probe to clarify the relationships and mechanisms between cancer immunotherapy and epigenetics.

Herein we report the first exploration of a dual-targeting drug design strategy to improve the efficacy of small-molecule cancer immunotherapy. New hybrids of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors and DNA alkylating nitrogen mustards that respectively target IDO1 and DNA were rationally designed. As the first-in-class examples of such molecules, they were found to exhibit significantly enhanced anticancer activity in vitro and in vivo with low toxicity. This proof-of-concept study has established a critical step toward the development of a novel and effective immunotherapy for the treatment of cancers.