12-O-Tetradecanoylphorbol-13-acetate (TPA), also commonly known as tetradecanoylphorbol acetate, tetradecanoyl phorbol acetate, and phorbol 12-myristate 13-acetate (PMA) is a diester of phorbol. It is a potent tumor promoter often employed in biomedical research to activate the signal transduction enzyme protein kinase C (PKC). The effects of TPA on PKC result from its similarity to one of the natural activators of classic PKC isoforms, diacylglycerol. TPA is a small molecule drug.
The epithelial–mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell–cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types. EMT is essential for numerous developmental processes including mesoderm formation and neural tube formation. EMT has also been shown to occur in wound healing, in organ fibrosis and in the initiation of metastasis in cancer progression.
Cyclacel Pharmaceuticals Inc. is a biotechnology firm based in Berkeley Heights, New Jersey and Dundee, Scotland, developing cancer treatments. Cyclacel was founded in 1996 by David Lane, PhD.
Casein kinase 2 (CK2/CSNK2) is a serine/threonine-selective protein kinase that has been implicated in cell cycle control, DNA repair, regulation of the circadian rhythm, and other cellular processes. De-regulation of CK2 has been linked to tumorigenesis as a potential protection mechanism for mutated cells. Proper CK2 function is necessary for survival of cells as no knockout models have been successfully generated.
ETV6 protein is a transcription factor that in humans is encoded by the ETV6 gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-oncogene in that it can fuse with other genes to drive the development and/or progression of certain cancers. However, ETV6 is also an anti-oncogene or tumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers.
A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes, thereby interfering with the JAK-STAT signaling pathway in lymphocytes.
ETV6-NTRK3 gene fusion is the translocation of genetic material between the ETV6 gene located on the short arm of chromosome 12 at position p13.2 and the NTRK3 gene located on the long arm of chromosome 15 at position q25.3 to create the (12;15)(p13;q25) fusion gene, ETV6-NTRK3. This new gene consists of the 5' end of ETV6 fused to the 3' end of NTRK3. ETV6-NTRK3 therefore codes for a chimeric oncoprotein consisting of the helix-loop-helix (HLH) protein dimerization domain of the ETV6 protein fused to the tyrosine kinase domain of the NTRK3 protein. The ETV6 gene codes for the transcription factor protein, ETV6, which suppresses the expression of, and thereby regulates, various genes that in mice are required for normal hematopoiesis as well as the development and maintenance of the vascular network. NTRK3 codes for Tropomyosin receptor kinase C a NT-3 growth factor receptor cell surface protein that when bound to its growth factor ligand, neurotrophin-3, becomes an active tyrosine kinase that phosphorylates tyrosine residues on, and thereby stimulates, signaling proteins that promote the growth, survival, and proliferation of their parent cells. The tyrosine kinase of the ETV6-NTRK3 fusion protein is dysfunctional in that it is continuously active in phosphorylating tyrosine residues on, and thereby continuously stimulating, proteins that promote the growth, survival, and proliferation of their parent cells. In consequence, these cells take on malignant characteristics and are on the pathway of becoming cancerous. Indeed, the ETV6-NTRK3 fusion gene appears to be a critical driver of several types of cancers. It was originally identified in congenital fibrosarcoma and subsequently found in mammary secretory carcinoma, mammary analogue secretory carcinoma of salivary glands, salivary gland–type carcinoma of the thyroid, secretory carcinoma of the skin, congenital fibrosarcoma, congenital mesoblastic nephroma, rare cases of acute myelogenous leukemia, ALK-negative Inflammatory myofibroblastic tumour, cholangiocarcinoma, and radiation-induced papillary thyroid carcinoma.
Crenolanib besylate is an investigational inhibitor being developed by AROG Pharmaceuticals, LLC. The compound is currently being evaluated for safety and efficacy in clinical trials for various types of cancer, including acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), and glioma. Crenolanib is an orally bioavailable benzamidazole that selectively and potently inhibits signaling of wild-type and mutant isoforms of class III receptor tyrosine kinases (RTK) FLT3, PDGFR α, and PDGFR β. Unlike most RTK inhibitors, crenolanib is a type I mutant-specific inhibitor that preferentially binds to phosphorylated active kinases with the ‘DFG in’ conformation motif.
Volasertib is an experimental small molecule inhibitor of the PLK1 protein being developed by Boehringer Ingelheim for use as an anti-cancer agent. Volasertib is the second in a novel class of drugs called dihydropteridinone derivatives.
Fedratinib, sold under the brand name Inrebic, is an anti-cancer medication used to treat myeloproliferative diseases including myelofibrosis. It is used in the form of fedratinib hydrochloride capsules that are taken by mouth. It is a semi-selective inhibitor of Janus kinase 2 (JAK-2). It was approved by the FDA on 16 August 2019.
Momelotinib (INN, formerly GS-0387, CYT-387) is an inhibitor of Janus kinases JAK1 and JAK2, acting as an ATP competitor with IC50 values of 11 and 18 nM, respectively. The inhibitor is significantly less active towards other kinases, including JAK3 (IC50 = 0.16 μM).
Dinaciclib (SCH-727965) is an experimental drug that inhibits cyclin-dependent kinases (CDKs). It is being evaluated in clinical trials for various cancer indications.
CUSP9 [Coordinated Undermining of Survival Paths] is one of several cancer treatment protocols using re-purposed older drugs to interfere with cancer cell's growth signaling rather than directly killing them with cytotoxic drugs. CUSP9 is a treatment specifically targeted to glioblastoma that adds to a traditional cancer cell killing drug, temozolomide, nine older, non-cytotoxic drugs to block growth factors that enhance or drive glioblastoma growth - aprepitant blocks NK-1, auranofin inhibits thioredoxin reductase, captopril inhibits angiotensin converting enzyme, celecoxib blocks cyclooxygenase-2, disulfiram blocks aldehyde dehydrogenase, itraconazole blocks Hedgehog signaling, minocycline inhibits metalloproteinase-2 and -9, quetiapine inhibits RANKL, sertraline inhibits translation-controlled tumor protein [TCTP]. These targets have been shown to be active in promoting glioblastoma growth.
Copanlisib is a drug which is approved by US FDA for the treatment of adult patients experiencing relapsed follicular lymphoma who have received at least two prior systemic therapies.
PD-1 inhibitors and PD-L1 inhibitors are a group of checkpoint inhibitor anticancer drugs that block the activity of PD-1 and PDL1 immune checkpoint proteins present on the surface of cells. Immune checkpoint inhibitors are emerging as a front-line treatment for several types of cancer.
Triciribine is a cancer drug which was first synthesized in the 1970s and studied clinically in the 1980s and 1990s without success. Following the discovery in the early 2000s that the drug would be effective against tumours with hyperactivated Akt, it is now again under consideration in a variety of cancers. As PTX-200, the drug is currently in two early stage clinical trials in breast cancer and ovarian cancer being conducted by the small molecule drug development company Prescient Therapeutics.
Entrectinib, sold under the brand name Rozlytrek, is an anti-cancer medication used to treat ROS1-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. It is a selective tyrosine kinase inhibitor (TKI), of the tropomyosin receptor kinases (TRK) A, B and C, C-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK).
Bemcentinib, also known as BGB324 or R428, is an experimental oral small molecule that is an inhibitor of AXL kinase. Bemcentinib was licensed from Rigel Pharmaceuticals by BerGenBio and currently undergoing six Phase II trials in various solid and hematological tumors as monotherapy and in combination with immunotherapy, chemotherapy, and targeted therapeutics.
Cerdulatinib is a small molecule SYK/JAK kinase inhibitor in development for treatment of hematological malignancies. It has lowest nM IC50 values against TYK2, JAK1, JAK2, JAK3, FMS, and SYK.
Pemigatinib, sold under the brand name Pemazyre, is an anti-cancer medication used for the treatment of bile duct cancer (cholangiocarcinoma). Pemigatinib works by blocking FGFR2 in tumor cells to prevent them from growing and spreading.
