Targeting tumor cell apoptosis and angiogenesis
Apoptosis (or programmed cell death) is an evolutionarily conservative process that maintains tissue homeostasis under cellular stress, DNA damage and immune surveillance. However, cancer cells can up-regulate anti-apoptotic proteins (such as Bcl-2 and Bcl-Xl) or down-regulate pro-apoptotic factors (such as Puma, Bax) to avoid apoptosis, thus promoting abnormal survival, therapeutic resistance and cancer recurrence. Therefore, targeting apoptosis can initiate programmed cell death of cancer cells and improve their response to anticancer drugs.
Tumors provide nutrients and oxygen through a new vascular system generated by angiogenesis, and discharge metabolic waste and carbon dioxide. Angiogenesis is triggered by anoxic processes that activate the expression of many growth factors. For example, vascular endothelial growth factor (VEGF) is a key growth factor that specifically recognizes vascular endothelial growth factor receptor (VEGFR) to induce the formation of new vascular system. Blocking VEGF/VEGFR signal to inhibit angiogenesis has become an important strategy for cancer treatment.
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Bcl-xL
Bcl-xL can inactivate the intrinsic apoptotic pathway and promote cell survival. The overexpression of Bcl-xL occurs in many tumor cells and is highly related to cancer treatment resistance, so Bcl-xL is a fully validated cancer target. However, low target participation and dose-limited thrombocytopenia limit the use of Bcl-xL inhibitors (such as ABT263 and AME 1155463) as safe and effective anticancer drugs.
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PARP1
Poly (ADP-ribose) polymerase 1 (PARP1) is involved in DNA damage repair to maintain genomic stability and is overexpressed in human cancer to escape apoptosis. Small molecular PARP1 inhibitors such as Nilapani, Rukapani and Orapani have been developed for cancer treatment. However, these inhibitors prevent the dissociation of PARP1 from DNA damage, which in turn blocks DNA replication and produce high cytotoxicity to normal cells.
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BCR‑ABL
Carcinogenic fusion kinase BCR-ABL can activate the anti-apoptotic protein Bcl-2 to protect mitochondria from DNA damage signals and prevent apoptosis in chronic myeloid leukemia (CML). BCR-ABL inhibitors such as Dashatinib, Punatinib and imatinib have been successfully used in the treatment of CML patients. However, because patients need persistent CML stem cells that depend on BCR-ABL kinase independent function for survival, they need lifelong drug administration. In addition, BCR-ABL mutations can also cause drug resistance.
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VEGFR-2
VEGFR-2 is the main VEGFR mediating the proliferation and angiogenesis of vascular endothelial cells. Targeting VEGFR2 is a promising strategy for cancer treatment. Shan et al developed PROTAC-2 and PROTAC-5 based on VEGFR-2 inhibitor S7, which showed effective VEGFR-2 elimination and anti-proliferation activity in human umbilical vein endothelial cells. In addition, these PROTAC have low cytotoxicity to HEK-293 cells (human embryonic kidney cells, VEGFR-2 negative) and show excellent safety to VEGFR-2 negative cells.
In addition to the above mentioned targets, PROATC can also target the following proteins related to tumor apoptosis and angiogenesis: AKT, Bcl-2, Bcl-6, BRD7/9, c-IAP, CK2, CRABP I/II, eEF2K, HDAC6, eIF4E, HDAC1/2/3, CBP/p300, Mcl-1, MDM2, PI3K, RIPK2, SGK3, SirT2.
Targeting tumor immunity and inflammation
In order to maintain cell survival, cancer cells induce inflammation and immune escape by reprogramming tumor microenvironments that regulate cell (regulatory T cells), B cell receptor (BCR) signal transduction and T cell receptor (TCR) signal transduction. A new immunotherapy of immune checkpoint inhibitors can alleviate immunosuppression and achieve immune-mediated tumor clearance. However, some patients have congenital or acquired resistance to immunotherapy. PROTAC targeting immunity and inflammation provides a new strategy to overcome these problems.
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PD-L1
Programmed death ligand 1 (PD-L1) is often overexpressed in cancer cells. PD-L1 on cancer cells binds to programmed death receptor 1 (PD-1) on T cells to counteract T cell activation signals, inhibit anti-tumor immunity and promote immune escape.
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BTK
Bruton tyrosine kinase (BTK) is a non-receptor tyrosine kinase that plays a key role in B cell development and immune response. BTK inhibitors such as ibutini can block BCR signal transduction and regulate innate / adaptive immunity for the treatment of chronic lymphoblastic leukemia (CLL) and mantle cell lymphoma (MCL). However, due to the Ibutini binding site (BTKC481S) mutation of BTK, many patients develop drug resistance.
In addition to the above mentioned targets, PROATC can also target the following proteins related to tumor immunity and inflammation: STAT3, FKBP12, HPK1, IDO1, IKZF1/3, IRAK4, ITK, JAK, CD147, PDE4, PDE δ, Pirin, PRC2, Lin28, PRMT5, Rpn13, SHP2, TBK1.
Targeting tumor metastasis
Tumor cells extravasate, spread and successfully colonize distant organs through the circulatory system to achieve metastasis, which is the cause of about 90% of cancer deaths worldwide. Epithelial-mesenchymal transition (EMT) is a key step in the process of metastasis, which can be activated by several upstream cellular signaling pathways, including the integrin / FAK/PI3K/AKT axis. PROTAC targeting EMT-related proteins has been developed to regulate cancer metastasis.
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FAK
Focal adhesion kinase (FAK) is one of the most important effector of integrin signal pathway. Overexpression of FAK is associated with poor clinical prognosis, which drives tumor invasion and migration by exerting kinase-dependent and independent functions. Researchers have developed several FAK kinase inhibitors, such as Defactinib, BI-4464 and PF-562271. However, currently developed inhibitors do not affect the key FAK kinase independent skeleton function.
In addition to the above mentioned targets, PROATC can also target the following proteins related to tumor metastasis: p38, Smad3, Src, TCF, TGF- β 1, β-catenin, IGF-1R.
PROTAC has become a very attractive cancer treatment technology. Although PROTAC has shown its clinical potential in cancer treatment, the development of PROTAC still needs to be further accelerated.