Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.

Article  PubMed  Google Scholar 

Park W, Chawla A, O’Reilly EM. Pancreatic cancer: a review. JAMA. 2021;326:851–62.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Luo W, Tao J, Zheng L, Zhang T. Current epidemiology of pancreatic cancer: challenges and opportunities. Chin J Cancer Res. 2020;32:705–19.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Manoochehri Khoshinani H, Afshar S, Najafi R. Hypoxia: a double-edged sword in cancer therapy. Cancer Invest. 2016;34:536–45.

Article  PubMed  CAS  Google Scholar 

Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178–96.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Jing X, Yang F, Shao C, Wei K, Xie M, Shen H, et al. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer. 2019;18:157.

Article  PubMed  PubMed Central  Google Scholar 

Serocki M, Bartoszewska S, Janaszak-Jasiecka A, Ochocka RJ, Collawn JF, Bartoszewski R. miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target. Angiogenesis. 2018;21:183–202.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Vaupel P, Thews O, Hoeckel M. Treatment resistance of solid tumors: role of hypoxia and anemia. Med Oncol. 2001;18:243–59.

Article  PubMed  CAS  Google Scholar 

Karakashev SV, Reginato MJ. Progress toward overcoming hypoxia-induced resistance to solid tumor therapy. Cancer Manag Res. 2015;7:253–64.

PubMed  PubMed Central  CAS  Google Scholar 

Kumar V, Gabrilovich DI. Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment. Immunology. 2014;143:512–9.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Baran N, Konopleva M. Molecular pathways: hypoxia-activated prodrugs in cancer therapy. Clin Cancer Res. 2017;23:2382–90.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Sun Y, Ding Y, Li D, Zhou R, Su X, Yang J, et al. Cyclic depsipeptide BE-43547A2: synthesis and activity against pancreatic cancer stem cells. Angew Chem Int Ed Engl. 2017;56:14627–31.

Article  PubMed  CAS  Google Scholar 

Villadsen NL, Jacobsen KM, Keiding UB, Weibel ET, Christiansen B, Vosegaard T, et al. Synthesis of ent-BE-43547A(1) reveals a potent hypoxia-selective anticancer agent and uncovers the biosynthetic origin of the APD-CLD natural products. Nat Chem. 2017;9:264–72.

Article  PubMed  CAS  Google Scholar 

Jacobsen KM, Villadsen NL, Tørring T, Nielsen CB, Salomón T, Nielsen MM, et al. APD-containing cyclolipodepsipeptides target mitochondrial function in hypoxic cancer cells. Cell Chem Biol. 2018;25:1337–49.e12

Article  PubMed  CAS  Google Scholar 

Liu C, Wang L, Sun Y, Zhao X, Chen T, Su X, et al. Probe synthesis reveals eukaryotic translation elongation factor 1 alpha 1 as the anti-pancreatic cancer target of BE-43547A2. Angew Chem Int Ed Engl. 2022;61:e202206953.

Guo JS, Li JJ, Wang ZH, Liu Y, Yue YX, Li HB, et al. Dual hypoxia-responsive supramolecular complex for cancer target therapy. Nat Commun. 2023;14:5634.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Chang J, Kim Y, Kwon H. Advances in identification and validation of protein targets of natural products without chemical modification. Nat Prod Rep. 2016;33:719–30.

Article  PubMed  CAS  Google Scholar 

Jafari R, Almqvist H, Axelsson H, Ignatushchenko M, Lundback T, Nordlund P, et al. The cellular thermal shift assay for evaluating drug target interactions in cells. Nat Protoc. 2014;9:2100–22.

Article  PubMed  CAS  Google Scholar 

Pai MY, Lomenick B, Hwang H, Schiestl R, McBride W, Loo JA, et al. Drug affinity responsive target stability (DARTS) for small-molecule target identification. Methods Mol Biol. 2015;1263:287–98.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Liao LX, Song XM, Wang LC, Lv HN, Chen JF, Liu D, et al. Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy. Proc Natl Acad Sci USA. 2017;114:E5986–E94.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Li J, Li S, Guo J, Li Q, Long J, Ma C, et al. Natural product micheliolide (MCL) irreversibly activates pyruvate kinase M2 and suppresses leukemia. J Med Chem. 2018;61:4155–64.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Liu CX, Yin QQ, Zhou HC, Wu YL, Pu JX, Xia L, et al. Adenanthin targets peroxiredoxin I and II to induce differentiation of leukemic cells. Nat Chem Biol. 2012;8:486–93.

Article  PubMed  CAS  Google Scholar 

Dai J, Liang K, Zhao S, Jia W, Liu Y, Wu H, et al. Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis. Proc Natl Acad Sci USA. 2018;115:E5896–E905.

Article  PubMed  PubMed Central  Google Scholar 

Lu X, Kang Y. Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res. 2010;16:5928–35.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15:234–48.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Vogel M, Xie L, Guan H, Tooze R, Maier T, Kostezka U, et al. FOXO1 repression contributes to block of plasma cell differentiation in classical Hodgkin lymphoma. Blood. 2014;124:3118–29.

Article  PubMed  CAS  Google Scholar 

Mudassar F, Shen H, O’Neill G, Hau E. Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas. J Exp Clin Cancer Res. 2020;39:208.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Fu J, Li T, Yang Y, Jiang L, Wang W, Fu L, et al. Activatable nanomedicine for overcoming hypoxia-induced resistance to chemotherapy and inhibiting tumor growth by inducing collaborative apoptosis and ferroptosis in solid tumors. Biomaterials. 2021;268:120537.

Article  PubMed  CAS  Google Scholar 

Yu JM, Sun W, Wang ZH, Liang X, Hua F, Li K, et al. TRIB3 supports breast cancer stemness by suppressing FOXO1 degradation and enhancing SOX2 transcription. Nat Commun. 2019;10:5720.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Yin H, Wang X, Zhang X, Zeng Y, Xu Q, Wang W, et al. UBE2T promotes radiation resistance in non-small cell lung cancer via inducing epithelial-mesenchymal transition and the ubiquitination-mediated FOXO1 degradation. Cancer Lett. 2020;494:121–31.

Article  PubMed  CAS