Selective inhibition of CDK4/6: A safe and effective strategy for developing anticancer drugs

The sustained cell proliferation resulting from dysregulation of the cell cycle and activation of cyclin-dependent kinases(CDKs)is a hallmark of cancer.The inhibition of CDKs is a highly promising and attractive strategy for the development of anticancer drugs.In particular,third-generation CDK inhibitors can selectively inhibit CDK4/6 and regulate the cell cycle by suppressing the G1 to S phase transition,exhibiting a perfect balance between anticancer efficacy and general toxicity.To date,three selective CDK4/6 inhibitors have received approval from the U.S.Food and Drug Administration(FDA),and 15 CDK4/6 inhibitors are in clinical trials for the treatment of cancers.In this perspective,we discuss the crucial roles of CDK4/6 in regulating the cell cycle and cancer cells,analyze the rationale for selectively inhibiting CDK4/6 for cancer treatment,review the latest advances in highly selective CDK4/6 inhibitors with different chemical scaffolds,explain the mechanisms associated with CDK4/6inhibitor resistance and describe solutions to overcome this issue,and briefly introduce proteolysis targeting chimera(PROTAC),a new and revolutionary technique used to degrade CDK4/6.

Tubeimoside-1 induces TFEB-dependent lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting mTOR

Programmed cell death ligand 1(PD-L1)/programmed cell death protein 1(PD-1)cascade is an effective therapeutic target for immune checkpoint blockade(ICB)therapy.Targeting PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor immunity.Using flow cytometry-based assay,we identify tubeimoside-1(TBM-1)as a promising antitumor immune modulator that negatively regulates PD-L1 level.TBM-1 disrupts PD-1/PD-L1 interaction and enhances the cytotoxicity of T cells toward cancer cells through decreasing the abundance of PD-L1.Furthermore,TBM-1 exerts its antitumor effect in mice bearing Lewis lung carcinoma(LLC)and B16 melanoma tumor xenograft via activating tumor-infiltrating T-cell immunity.Mechanistically,TBM-1 triggers PD-L1 lysosomal degradation in a TFEB-dependent,autophagy-independent pathway.TBM-1 selectively binds to the mammalian target of rapamycin(m TOR)kinase and suppresses the activation of m TORC1,leading to the nuclear translocation of TFEB and lysosome biogenesis.Moreover,the combination of TBM-1 and anti-CTLA-4 effectively enhances antitumor T-cell immunity and reduces immunosuppressive infiltration of myeloid-derived suppressor cells(MDSCs)and regulatory T(Treg)cells.Our findings reveal a previously unrecognized antitumor mechanism of TBM-1 and represent an alternative ICB therapeutic strategy to enhance the efficacy of cancer immunotherapy.

Sodium cantharidinate,a novel anti-pancreatic cancer agent that activates functional p53

Despite the use of many types of chemotherapies for pancreatic cancer, optimal efficacy has not been obtained so far. Pancreatic cancer shows a high incidence of TP53 mutations, inactivating its tumor suppressor activity. In this study, we identified sodium cantharidinate as a novel, potential anti-pancreatic cancer agent that activates p53 function. Sodium cantharidinate reduced the viability of pancreatic cancer cells, including the human primary pancreatic cancer cells, PANC-1, As PC-1, SW1990 and BXPC-3, in a dose-dependent manner. Sodium cantharidinate induced apoptosis and DNA damage of pancreatic cancer cells. Furthermore, proteome-wide sequencing analysis detected a marked perturbation in p53 signaling pathway on PANC-1 cells upon sodium cantharidinate. Consistent with the previous results, sodium cantharidinate treatment decreased Bcl-2 and mitochondrial cytochrome-c protein expression, as well as phosphorylation of MDM2;meanwhile, it increased the levels of cleaved-caspase-3,cleaved-caspase-9, cleaved-PARP, Bax, and phosphorylated p53, thus inducing the apoptosis of pancreatic cancer cells. The p53-activating effect of sodium cantharidinate was strongly abrogated by treatment with TP53-targeting sh RNA. Moreover, sodium cantharidinate inhibited neoplasm growth via the JAK2-STAT3 pathway, which was inhibited by sh RNA-TP53 and triggered by combination with gemcitabine. Combination therapy indicated that sodium cantharidinate and gemcitabine synergistically reduced ex vivo and in vivo growth of pancreatic neoplasm. Further docking studies revealed the different binding fates of sodium cantharidinate to activate wild-type p53 function. Thus, sodium cantharidinate could be a potential agent with promising anti-pancreatic cancer efficacy.

Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents

Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1)have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy.Despite the inherent advantages of small-molecule inhibitors over antibodies,the discovery of small-molecule inhibitors has fallen behind that of antibody drugs.Based on docking studies between small molecule inhibitor and PD-L1 protein,changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein,which was not reported before.A series of novel phthalimide derivatives from structure-based rational design was synthesized.P39 was identified as the best inhibitor with promising activity,which not only inhibited PD-1/PD-L1 interaction(IC_(50)=8.9 nmol/L),but also enhanced killing efficacy of immune cells on cancer cells.Co-crystal data demonstrated that P39 induced the dimerization of PD-L1 proteins,thereby blocking the binding of PD-1/PD-L1.Moreover,P39 exhibited a favorable safety profile with a LD_(50)>5000 mg/kg and showed significant in vivo antitumor activity through promoting CD8^(+)T cell activation.All these data suggest that P39 acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells.

Development and clinical advancement of small molecules for ex vivo expansion of hematopoietic stem cell

Hematopoietic stem cell(HSC) transplantation is the only curative therapy for many diseases.HSCs from umbilical cord blood(UCB) source have many advantages over from bone marrow.However,limited HSC dose in a single CB unit restrict its widespread use.Over the past two decades,ex vivo HSC expansion with small molecules has been an effective approach for obtaining adequate HSCs.Till now,several small-molecule compounds have entered the phase Ⅰ/Ⅱ trials,showing safe and favorable pharmacological profiles.As HSC expansion has become a hot topic over recent years,many newly identified small molecules along with novel biological mechanisms for HSC expansion would help solve this challenging issue.Here,we will give an overview of HSC biology,discovery and medicinal chemistry development of small molecules,natural products targeting for HSC expansion,and their recent clinical progresses,as well as potential protein targets for HSC expansion.