PI3K is called Phosphatidylinositol 3-kinase (phosphatidylinositol 3-kinase), which is involved in the regulation of various cellular functions such as cell proliferation, differentiation, apoptosis and glucose transport. An increase in PI3K activity is often associated with a variety of cancers. Phosphorylation and activation of AKT after PI3K activation, localizes it in the plasma membrane. Signals are transmitted through AKT to different downstream targets, such as activation of CREB, inhibition of p27, localization of FOXO to the cytoplasm, activation of PtdIns-3ps, and activation of mTOR (affecting transcription of p70 or 4EBP1). In a variety of cancers, the PI3K/AKT/mTOR pathway is over-activated, and Akt with sustained-activity promotes proliferation of unregulated cell, therefore reducing tumor cell apoptosis and promoting proliferation. At present, there are three PI3K inhibitors listed on the market, namely Idelalisib of Gilead, Copanlisib of Bayer, and Duvelisib, which was just approved in September this year, for the treatment of lymphoma. Duvelisib is the first oral PI3K inhibitor to be shown as a monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. As a monotherapy, it also shows significant clinical effects in patients with dual-resistance follicular lymphoma.
| Phase | Code Name (CD) | Generic Name (GN) | Organization | Condition |
| Phase I | XC-302 | Puquitinib | Zhejiang Medicine (Originator); | Lymphoma, non-Hodgkin |
| Phase I | SAR-245408; XL-147; 60ES45KTMK (UNII code) | Pilaralisib (USAN; Rec INN) | Sanofi; Exelixis (Originator); | Glioblastoma multiforme; Cancer, breast; Cancer, lung (non-small cell) (NSCLC); Lymphoma; Cancer, solid tumor; Cancer, endometrium; Cancer |
| Phase I | P-7170 | Panulisib (Rec INN) | Piramal Enterprises (Originator); | Inflammation; Cancer, solid tumor |
| Phase I | RV-1729 | RespiVert (Originator); | Chronic obstructive pulmonary disease (COPD); Asthma | |
| Phase I | CC-1126; SF-1126 | SignalRx; University of California, San Diego; Semafore Pharmaceuticals (Originator); | Neuroblastoma; Cancer, head and neck (squamous cell carcinoma); Cancer, liver (hepatocellular carcinoma); Cancer | |
| Phase I | GDC-0941; RG-7321 | Pictilisib (USAN; Rec INN); Pictrelisib (former INN) | Genentech (Originator); Chugai Pharmaceutical (Originator); Piramed (Originator); | Cancer, breast metastatic; Cancer, breast; Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Lymphoma, non-Hodgkin |
| Phase I | PKI-179 | Pfizer (Originator); | Cancer | |
| Phase I | WX-037 | UCB (Originator); | Cancer, solid tumor | |
| Phase I | 2126458; GSK-2126458; GSK-458 | Omipalisib (Prop INN; USAN) | GlaxoSmithKline (Originator); | Idiopathic pulmonary fibrosis; Lymphoma; Cancer, solid tumor |
| Phase I | PF-04691502; PF-1502; PF-4691502; PF-502 | Pfizer (Originator); | Cancer, breast; Cancer, endometrium | |
| Phase I | CAL-120; GS-9820 | Acalisib (Rec INN) | Icos (Originator); Gilead; | Cancer, solid tumor; Hematologic-blood cancer |
| Phase I/II | SAR-245409; XL-765 | Voxtalisib hydrochloride (USAN; Rec INN) | Sanofi; Exelixis (Originator); | Malignant neoplasms; Glioblastoma multiforme; Cancer, breast; Cancer, lung (non-small cell) (NSCLC); Lymphoma; Cancer, solid tumor; Cancer, ovary; Lymphoma, non-Hodgkin; Cancer |
| Phase I/II | GSK-2636771 | GlaxoSmithKline (Originator); | Melanoma, metastatic; Cancer, prostate (castration-resistant); Cancer, solid tumor | |
| Phase I/II | ZSTK-474 | Japanese Foundation for Cancer Research; Zenyaku Kogyo (Originator); | Cancer, solid tumor; Rheumatoid arthritis; Cancer | |
| Phase I/II | TG-100-115; TG-100115 | Sanofi (Originator); | Myocardial infarction; Asthma; Cancer | |
| Phase I/II | BGT-226; NVP-BGT-226; NVP-BGT226 | Novartis (Originator); | Cancer, solid tumor | |
| Phase II | INK-1117; MLN-1117; TAK-117; 43J9Q56T3W (UNII code) | Serabelisib (Rec INN) | Millennium Pharmaceuticals (Originator); | Cancer, gastrointestinal; Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Cancer, endometrium; Triple negative breast cancer; Cancer, kidney (renal cell carcinoma, clear cell) |
| Phase II | AMG-319 | Cancer Research UK; Amgen (Originator); | Cancer, head and neck (squamous cell carcinoma); Cancer, solid tumor; Hematologic-blood cancer | |
| Phase II | AZD-8186 | AstraZeneca (Originator); | Cancer, prostate (castration-resistant); Cancer, solid tumor; Cancer, lung (non-small cell) (NSCLC) (squamous cell carcinoma); Triple negative breast cancer | |
| Phase II | NSC-350625; ONC-201; ONC201/TIC10; TIC-10 | University of Pennsylvania (Originator); Oncoceutics; Wayne State University (Originator); ChemDiv (Originator); Pennsylvania State University (Originator); Oncoceutics (Originator); Harvard Medical School (Originator); Oncalis; | Cancer, breast metastatic; Leukemia, acute myeloid; Neuroendocrine cancer; Glioblastoma multiforme; Multiple myeloma; Cancer, solid tumor; Cancer, endometrium; Leukemia, acute lymphocytic; Lymphoma, non-Hodgkin; Triple negative breast cancer; Myelodysplasia; Cancer | |
| Phase II | UCB-5857; 64CW205BDD (Unique Ingredient Identifier (UNII) code) | Seletalisib (Rec INN) | UCB (Originator); | Sjogren syndrome; PASLI disease; Psoriasis; Immunological Disorders |
| Phase II | KRX-0601; KW-2401; NSC-638850; UCN-01 | 7-Hydroxystaurosporine | National Cancer Institute; Kyowa Hakko Kirin (Originator); Keryx; | Leukemia, hairy cell; Lymphoma, T-cell; Lymphoma; Cancer, ovary; Leukemia, myeloid; Melanoma; Cancer; Leukemia, chronic lymphocytic; Cancer, lung (small cell) (SCLC) (extensive) |
| Phase II | DJM-166; DJM-2-166; NSC-722134; PX-866 | Sonolisib (Rec INN) | Seattle Genetics; University of Arizona (Originator); | Cancer, head and neck (squamous cell carcinoma); Glioblastoma multiforme; Cancer, prostate (castration-resistant); Cancer, solid tumor; Cancer, lung (non-small cell) (NSCLC) (squamous cell carcinoma); Cancer, colorectal metastatic; Melanoma; Cancer |
| Phase II | CRx-191 | Mometasone furoate/nortriptyline hydrochloride | EPIRUS Biopharmaceuticals (Originator); | Psoriasis |
| Phase II | CRx-197 | Loratadine/nortriptyline hydrochloride | EPIRUS Biopharmaceuticals (Originator); | Dermatitis, atopic; Psoriasis |
| Phase II | BEZ-235; NVP-BEZ-235; RTB-101 | Dactolisib (USAN; Rec INN) | Novartis (Originator); PureTech; Johann Wolfgang Goethe Universitaet; resTORbio; | Carcinoma, transitional cell; Cancer, pancreas (neuroendocrine); Infection, respiratory tract; Cancer, breast; Cancer, prostate; Cancer, prostate (castration-resistant); Glioma; Leukemia; Cancer, kidney (renal cell carcinoma, clear cell); Perivascular epithelioid cell tumors (PEComas) |
| Phase II | CRx-170 | Prednisolone/nortriptyline | EPIRUS Biopharmaceuticals (Originator); | Pain, chronic |
| Phase II | BKM-120; NVP-BKM120 | Buparlisib (Rec INN) | Novartis (Originator); Yonsei University; Memorial Sloan-Kettering Cancer Center; Prince of Songkla University; Hospices Civils de Lyon; Hangzhou Adlai Nortye Pharm Technol; | Cancer, pancreas; Lymphoma, primary central nervous system; Cancer, bladder (urothelial carcinoma, transitional cell); Cancer, head and neck (squamous cell carcinoma); Glioblastoma multiforme; Cancer, thymus; Cancer, liver (hepatocellular carcinoma); Cancer, breast; Cancer, prostate (castration-resistant); Cancer, esophagus; Cancer, lung (non-small cell) (NSCLC); Lymphoma, diffuse large B-cell; Lymphoma, follicular; Cancer, endometrium; Melanoma; Gastrointestinal stromal tumor (GIST); Cancer, colorectal; Lymphoma, mantle cell; Cancer, ovary (serous); Cancer, thyroid, differentiated; Cancer; Leukemia, chronic lymphocytic; Myelofibrosis |
| Phase II | PF-05212384; PF-384; PF-5212384; PKI-587; 96265TNH2R (UNII code) | Gedatolisib (USAN; Rec INN) | Institut Curie; Pfizer (Originator); | Cancer, pancreas; Leukemia, acute myeloid; Cancer, breast; Cancer, lung (non-small cell) (NSCLC); Cancer, head and neck; Cancer, solid tumor; Cancer, lung (non-small cell) (NSCLC) (squamous cell carcinoma); Cancer, colorectal metastatic; Cancer, endometrium; Triple negative breast cancer; Cancer, colorectal |
| Phase II | G-038390; G-038390.1; GDC-0980; GDC-0980.1; R-7422; RG-7422 | Apitolisib (USAN; Rec INN) | Genentech (Originator); Roche (Originator); | Cancer, kidney (clear cell sarcoma); Cancer, breast; Cancer, prostate (castration-resistant); Cancer, endometrium; Lymphoma, non-Hodgkin |
| Phase II/III | CDZ-173; CDZ-173-NX; L22772Z9CP (UNII code) | Leniolisib (USAN; Rec INN) | Novartis (Originator); | Immunological genetic disorders; Sjogren syndrome |
| Phase III | RP-5307; TGR-1202; TGR-1202 PTSA; FU8XW5V3FS (UNII code); RP-5264 (free base) | Umbralisib tosylate (Prop INNM; USAN) | Rhizen Pharmaceuticals (Originator); TG Therapeutics; Incozen; Vanderbilt University; DNSK International; | Waldenstrom macroglobulinemia; Multiple sclerosis; Lymphoma, Hodgkin; Lymphoma; Cancer, solid tumor; Polycythemia vera; Lymphoma, diffuse large B-cell; Lymphoma, follicular; Lymphoma, B-cell; Autoimmune disease; Hematologic-blood cancer; Lymphoma, mantle cell; Cancer; Leukemia, chronic lymphocytic; Myelofibrosis |
| Phase III | 317615; DB-102; LY-317615 | Enzastaurin hydrochloride (Rec INNM; USAN) | Denovo Biopharma; Stanford University; National Cancer Institute; Denovo Biopharma; Lilly (Originator); | Cancer, pancreas; Waldenstrom macroglobulinemia; Hypertension, pulmonary arterial; Glioblastoma multiforme; Cancer, breast; Cancer, prostate; Multiple myeloma; Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Lymphoma, diffuse large B-cell; Cancer, kidney (renal cell carcinoma); Cancer, ovary; Glioma; Lymphoma, non-Hodgkin; Cancer, colorectal; Lymphoma, mantle cell; Cancer |
| Phase III | ON-01910Na; ON-1910Na; Onc-01910; SyB C-1101; SyB L-1101 | Rigosertib sodium (USAN; Rec INN) | Pint Pharma; Nat Heart, Lung, and Blood Institute; Temple University (Originator); Onconova (Originator); SymBio; | Cancer, pancreas; Leukemia, acute myeloid; Lymphoma; Cancer, head and neck; Cancer, solid tumor; Cancer, ovary; Leukemia, acute lymphocytic; Leukemia, juvenile myelomonocytic; Myelodysplasia; Myelofibrosis |
Figure 1 A schematic diagram depicting the most representative signaling of the PI3K/AKT pathway
Mechanism and Function of PI3K
The pleckstrin homology domain of AKT binds directly to PtdIns (3, 4, 5) P3 and PtdIns (3, 4) P2, which is produced by activated PI3-kinase. Since PtdIns (3, 4, 5) P3 and PtdIns (3, 4) P2 are restricted to the plasma membrane, which cause the AKT to translocate to the plasma membrane. Similarly, phosphoinositide-dependent kinase-1 (PDK1 or seldom known as PDPK1) also contains a pleckstrin homology domain that binds directly to PtdIns (3, 4, 5) P3 and PtdIns (3, 4) P2, causing it to translocate to the plasma membrane after activating PI3-kinase. The interaction of activated PDK1 and AKT allows AKT to be phosphorylated by PDK1 on threonine 308, resulting in partial activation of AKT. Complete activation of AKT occurs when phosphorylation of serine 473 by the TORC2 complex of mTOR protein kinase.
PI 3 kinase is involved in a diverse array of cellular functions, including cell growth, proliferation, differentiation, movement, survival, and intracellular trafficking. Many of these functions involve the ability of class I PI3-kinases, such as the PI3K/AKT/mTOR pathway to activate protein kinase B (PKB, also known as Akt). The p110δ and p110γ isoforms regulate different aspects of the immune response. PI3 kinase is also a key component of the insulin signaling pathway. Therefore, people are interested in the role of PI 3-kinase signaling in diabetes.
Conclusion
PI3K/Akt/mTOR signaling pathway, which is one of the most important pathways for cell survival, plays an important role in promoting cell growth, proliferation, cell movement, invasion, inhibition of apoptosis, and promotion of angiogenesis. PI3Ks have been shown to be a potential tumor drug target, and anti-tumor treatment prospects are promising. At the same time, dual-target inhibitors (such as PI3K/mTOR) have become a research hotspot in recent years, and it is believed that they will land in the global market of anti-cancer drug in the near future. In the next few years, research on PI3K / mTOR biology will certainly uncover additional surprises and new ways to ameliorate human disease.
References
1. Fruman, D. A., & Rommel, C. (2014). PI3K and cancer: lessons, challenges and opportunities. Nature reviews Drug discovery, 13(2), 140.
2. Dibble, C. C., & Cantley, L. C. (2015). Regulation of mTORC1 by PI3K signaling. Trends in cell biology, 25(9), 545-555.
3. Fruman, D. A., Chiu, H., Hopkins, B. D., Bagrodia, S., Cantley, L. C., & Abraham, R. T. (2017). The PI3K pathway in human disease. Cell, 170(4), 605-635.
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