Entospletinib (GS-9973) is an adenosine triphosphate competitive inhibitor of Syk that disrupts kinase activity, which is currently in clinical trials for multiple B-cell malignancies. The most common treatment-emergent serious adverse events included dyspnea, pneumonia, febrile neutropenia, dehydration, and pyrexia.

Antroquinonol is isolated from Antrodia camphorata, a camphor tree mushroom, and is a valuable traditional Chinese herbal medicine that exhibits pharmacological activities against several diseases, including cancer. Antroquinonol displayed anticancer activity against hepatocellular carcinoma cell lines through activation of 5′ adenosine-monophosphate-activated protein kinase and inhibition of the mammalian target of rapamycin (mTOR) pathway. Antroquinonol also exhibits anticancer activity in human pancreatic cancers through inhibition of the phosphoinositide-3 kinase (PI3K)/Akt/mTOR pathway, which in turn downregulates the expression of cell cycle regulators. The translational inhibition causes a G1 arrest of the cell cycle and ultimately mitochondria-dependent apoptosis. A study on the A549 pulmonary adenocarcinoma cell line demonstrated that antroquinonol-induced apoptosis was associated with disrupted mitochondrial membrane potential and activation of caspase-3 and poly ADP ribose polymerase cleavage. Moreover, antroquinonol treatment downregulated the expression of B-cell lymphoma 2 proteins, which was correlated with decreased PI3K and mTOR protein levels, without altering the levels of pro- or antiapoptotic proteins. Antroquinonol is currently in phase II trials (USA and Taiwan) for the treatment of non-small-cell lung carcinoma (NSCLC), atopic dermatitis; colorectal cancer; hepatitis B; hyperlipidaemia; pancreatic cancer. Antroquinonol was also approved for drug clinical trials by the Russian Ministry of Health (MoH). The MoH gave permission to test the efficacy and safety of Phase II clinical trials in patients with acute myeloid leukemia in Russia. Antroquinonol received the Orphan Drug Designation by the FDA in treatment of pancreatic cancer, liver cancer and acute myeloid leukaemia.

Idasanutlin (RG-7388) is a second-generation, orally bioavailable, selective p53-MDM2 antagonist. MDM2 is an important negative regulator of the p 53 tumor suppressor and is expressed at high levels in a large proportion of acute myeloid leukemia (AML). Blocking the MDM2-p53 interaction stabilizes p53 and activates p-53 mediated cell death and inhibition cell growth. Idasanutlin is under clinical trial in phase III for treatment AML and in combinations with others drugs in phase I/II for treatment of multiple myeloma.

APR-246 is a methylated form of PRIMA-1, 2-hydroxymethyl-2-methoxymethyl-aza-bicyclo[2.2.2]octan-3-one (PRIMA-1MET). APR-246, is a prodrug that is converted to the Michael acceptor methylene quinuclidinone (MQ) that binds covalently to cysteines in p53, leading to refolding and restoration of wild type p53 function. MQ also targets the cellular redox balance by inhibiting thioredoxin reductase (TrxR1) and depleting glutathione. APR-246 can rescue mutant forms of the p53 family members p63 and p73 that share high sequence homology with p53. APR-246 has demonstrated compelling pre-clinical antitumor activity in a wide variety of solid and hematological (blood) tumors, including ovarian cancer, small cell lung cancer, esophageal cancer and acute myeloid leukemia (AML), among others. Furthermore, strong synergy has been seen with both traditional anticancer agents, such as chemotherapy, as well as newer mechanism-based anticancer drugs. A Phase I clinical study has been completed, demonstrating a favorable safety profile and both biological and clinical responses in hematological tumors with mutations in the p53 gene. A Phase Ib clinical study in combination with full dose chemotherapy (carboplatin and pegylated liposomal doxorubicin) has also been completed, demonstrating a favorable safety profile in patients with high-grade serous ovarian cancer (HGSOC). APR-246 is currently in a Phase II clinical trial in patients with HGSOC, and additional Phase Ib clinical studies of APR-246 in other cancer indications are planned.

R428 (BGB324) is an inhibitor of Axl with IC50 of 14 nM. R428 was originated in Rigel Pharmaceuticals and was licensed to BerGenBio, which initiated clinical trials for the treatment of non-small cell lung cancer, metastatic melanoma and acute myeloid leukaemia.

Echinomycin is a cyclic peptide of the family of quinoxaline antibiotics that was originally isolated from Streptomyces echinatus. It is thought to act as a bifunctional DNA intercalator. Echinomycin has a binding site size of four base pairs. The strong binding sites for echinomycin contain the central two-base-pair sequence 5'-CG-3'. Echinomycin interferes with HIF-1 DNA binding in a sequence-specific fashion. It was brought into clinical trials by the NCI 20 years ago based on its antitumor activity. It has been extensively tested in phase I-II clinical trials. Nausea, vomiting, reversible liver enzyme abnormalities, and allergic reactions were the most common toxicities encountered. However, minimal or no antitumor activity was found in phase II clinical trials.

CNDAC (TAK-109) is an analog of the nucleoside deoxycytidine with potential antineoplastic activity. CNDAC is incorporated into DNA and induces single-strand breaks, which are converted into double-strand breaks (DSBs) when cells go through a second S phase. This results in the cell cycle arrest in the S and G2/M phases, DNA fragmentation, and tumor cell apoptosis. Sapacitabine, a prodrug of CNDAC, is being developed by the US biotechnology company Cyclacel for the treatment of hemalogical cancers and solid tumors.