Overview of PI3K inhibitors in research competition


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 discovery13(2), 140.

2. Dibble, C. C., & Cantley, L. C. (2015). Regulation of mTORC1 by PI3K signaling. Trends in cell biology25(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. Cell170(4), 605-635.

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