Silmitasertib (CX-4945) is a potent and selective orally bioavailable small molecule inhibitor of Casein kinase II (CK2). The antiproliferative activity of CX-4945 against cancer cells correlated with expression levels of the CK2α catalytic subunit. CX-4945 caused cell-cycle arrest and selectively induced apoptosis in cancer cells relative to normal cells. When administered orally in murine xenograft models, CX-4945 was well tolerated and demonstrated robust antitumor activity. Senhwa Biosciences is developing silmitasertib for the treatment of cholangiocarcinoma, other solid tumours, Castleman's disease (giant lymph node hyperplasia) and multiple myeloma. The compound was originally developed by Cylene Pharmaceuticals. Phase Ib/II development is underway in the US and South Korea for the treatment of cholangiocarcinoma, and development in the remaining indications is at the phase I stage. As at July 2016, no recent reports of development had been identified for phase-I development in Giant-lymph-node-hyperplasia in USA (PO, Capsule), phase-I development in Multiple-myeloma in USA (PO, Capsule), phase-I development in Solid-tumours (Late-stage disease) in USA (PO, Capsule).

Imexon (INN, trade name Amplimexon) is a substance that is being studied in the treatment of some types of cancer, including pancreatic, lung, breast, prostate, melanoma, and multiple myeloma. Imexon is a thiol-binding small molecule which induces mitochondrial oxidation, a loss of membrane potential and cytochrome C, leading to apoptosis.

Atiprimod is an oral azaspirane which was initially developed by Smith Kline and French Laboratories for treating rheumatoid arthritis (discontinued in phase I). Due to its anti-inflammatory, antineoplastic, and antiangiogenic properties, the drug was tested in patients with Neuroendocrine Carcinoma and Multiple Myeloma and reached phase II (discontinued). In vitro studies revealed that atiprimod exerts its action by inhibiting the phosphorylation of signal transducer and activator of transcription 3 (STAT3), blocking the signalling pathways of interleukin-6 and vascular endothelial growth factor (VEGF) and downregulating the anti-apoptotic proteins Bcl-2, Bcl-XL, and Mcl-1, thereby inhibiting cell proliferation, inducing cell cycle arrest, and inducing apoptosis.

Perifosine is an orally active alkyl-phosphocholine compound with potential antineoplastic activity. Perifosine is an Akt inhibitor, which targets the pleckstrin homology domain of Akt, thereby preventing its translocation to the plasma membrane. Perifosine exerts Akt-dependent and Akt-independent effects, and although many preclinical studies have documented Akt inhibition by perifosine, clinical validation of these findings is lacking. Perifosine is in phase II and III clinical trials for the treatment of neuroblastoma, glioblastoma multiforme and other solid tumors.

Darinaparsin is a novel mitochondrial-targeted agent being developed for the treatment of various hematologic and solid cancers. In a Phase II study in the US, intravenous darinaparsin demonstrated evidence of clinical activity in malignant lymphoma, and in particular peripheral T-cell lymphoma (PTCL). Darinaparsin was granted Orphan Drug Designation in the US and Europe as a treatment of PTCL. The oral formulation is also being tested in Phase I for the treatment of solid tumors. Darinaparsin induces G2/M cell cycle arrest and apoptosis in tumor cells, primarily through disruption of mitochondrial functions, increased reactive oxygen species (ROS) production and modulation of signal transduction pathways.

R-etodolac (SDX-101) is the non-cyclooxygenase 2-inhibiting R-enantiomer of the non-steroid anti-inflammatory drug etodolac (1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid). The absolute configuration of the enantiomer is R-(-)-etodolac. R-etodolac specifically bound retinoid X receptor (RXRalpha), inhibited RXRalpha transcriptional activity, and induced its degradation by a ubiquitin and proteasome-dependent pathway. In addition R-etodolac can disrupt the beta-catenin signaling pathway. R-etodolac exerts antineoplastic properties. R-etodolac was in phase 2 studies for the treatment of hematologic malignancies however development was discontinued.

A second generation of HDACs, synthetic benzamide-containing HDACs such as Tacedinaline (CI-994), have reached phase I and II clinical trials. It has been investigated for its applications to the treatment of cancers such as Breast cancer and Colorectal cancer. Tacedinaline has been in phase III clinical trials by Pfizer for the treatment of advanced non-small cell lung cancer and pancreatic cancer combined with gemcitabine. However, this research has been discontinued. Mechanism of Action: Angiogenesis inhibitors; Histone deacetylase inhibitors. Pharmacokinetics showed that CI-994 absorption and disposition were unaffected by carboplatin and paclitaxel coadministration.

2-Methoxyestradiol (2ME2) is a natural metabolite of endogenous estrogen hormone 17β-estradiol in human and devoid of estrogenic activity. It is a drug that prevents the formation of new blood vessels that tumors need in order to grow (angiogenesis). It has undergone Phase 1 clinical trials against breast cancers. Preclinical models also suggest that 2ME2 could also be effective against inflammatory diseases such as rheumatoid arthritis. 2-Methoxyestradiol is an angiogenesis inhibitor, and has been shown to attack both tumor cells and their blood supply in preclinical testing. Presently, it is an investigational drug under various phases of clinical trials alone or in combination therapy. Its anticancer activity has been attributed to its antitubulin, antiangiogenic, pro-apoptotic and ROS induction properties. 2-Methoxyestradiol shows strong cytotoxic effect on estrogen dependent and independent cancerous cells, which is mainly due to disruption of microtubule process and p53 induced apoptosis through caspase, reactive oxygen species (ROS), superoxide dismutase (SOD) and nitric oxide synthase. 2-Methoxyestradiol inhibits tubulin polymerisation by binding to colchicine binding site of the tubulin and arrests cell cycle at G2/M-phase.

Filanesib is a highly selective, targeted KSP inhibitor with a mechanism of action distinct from currently available myeloma therapies such as immunomodulatory drugs (IMiDs®) and proteasome inhibitors. Across multiple studies, filanesib has demonstrated activity in heavily pretreated multiple myeloma patients, with a consistent safety profile including no drug-induced peripheral neuropathy and limited non-hematologic toxicity. Adverse events are generally limited to transient, non-cumulative and predominantly asymptomatic myelosuppression (decreases in blood counts) when supportive measures are used. Alpha 1-acid glycoprotein (AAG), a plasma protein, is a potential patient selection marker for filanesib. AAG is undergoing further investigation in clinical trials and could represent the first patient selection marker for a myeloma therapy. Filanesib is in Phase II for Multiple myeloma treatment.

Tanespimycin (17-allylamino-17-demethoxygeldanamycin, 17-AAG) is a synthetic analogue of geldanamycin, an antibiotic first purified in 1970 from Streptomyces hygroscopicus. Tanespimycin is an Hsp90 inhibitor that has demonstrated the potential to disrupt the activity of multiple oncogenes and cell signaling pathways implicated in tumor growth, including HER2, a key pathway in breast cancer. Tanespimycin was being under development by Kosan Biosciences. It was in phase 3 clinical development with bortezomib for the treatment of multiple myeloma (MM). However, in 2010 the company halted development of tanespimycin, during late-stage clinical trials as a potential treatment for multiple myeloma. While no definitive explanation was given, it has been suggested that Bristol-Myers Squibb halted development over concerns of the financial feasibility of tanespimycin development given the 2014 expiry of the patent on this compound, and the relative expense of manufacture.