Marizomib is a natural beta-lactone produced by the marine bacterium Salinispora tropica. Marizomib has a broad inhibition profile for the 20S proteasome and has been shown to inhibit the CT-L (beta5) CT-T-laspase-like (C-L, beta1) and trypsin-like (T-L, beta2) activities of the 20S proteasome. The drug is being tested in phase II clinical trials for the treatment of Multiple Myeloma and Malignant Glioma and in phase I in patients with Non-small Cell Lung Cancer, Pancreatic Cancer, Melanoma or Lymphoma

Ergosterol endoperoxide is a derivative of ergosterol. It has been isolated from a variety of fungi, yeast, lichens and sponges. Ergosterol endoperoxide has been shown to inhibit the growth of some cancer cells and to induce apoptosis of HL60 human leukemia cells. Ergosterol endoperoxide also decreases lipid peroxidation of rat liver microsomes and suppresses the proliferation of mouse and human lymphocytes stimulated with mitogens. It has been reported as having immunosuppressive, antiplasmodial, antimycobacterial, antiviral, anti-inflammatory and antitumoural properties. The interaction of Trypanosoma cruzi with ergosterol peroxide in vitro resulted in a strong lytic activity possibly due to the disruption of the parasite membrane.

MLN120B is a potent and selective inhibitor of IKK-beta, which competes with ATP at the ATP-binding site. MLN120B has been shown to be a promising treatment in preclinical models of rheumatoid arthritis, non-Hodgkin's lymphoma and multiple myeloma.

KDM5-C70 is an ethyl ester derivative of KDM5-C49, which is a potent and selective inhibitor of Jumonji AT-Rich Interactive Domain 1 (JARID1) histone demethylases. The highly polar carboxylate group of KDM5-C49 restricts its cellular permeability; therefore KDM5-C70 was developed as a pro-drug, masking the polarity of the acid group of the KDM5-C49, for cellular assays and in vivo use. It has IC50 <1 uM for KDM5B (or PLU1) and UTX in histone lysine demethylase AlphaLISA assays, very good selectivity over JMJD1B, JMJD2A, JMJD2B and JMJD3. It has IC50 <1 uM for inhibiting demethylation of H3K4 in U2OS human osteosarcoma cell line. KDM5-C70 also suppresses human breast adenocarcinoma MCF7 tumor cell proliferation with IC50 < 1 uM. KDM5-C70 has shown antiproliferative effects in myeloma cells, leading to genome-wide elevation of H3K4me3 levels. KDM5-C70 treatment increased global H3K4me3 levels in HeLa cells. In this case, KDM5-C70 led to decreased 3′UTR length of DICER1. Although the cellular potency of KDM5-C70 is weak and about one to two orders of magnitude beyond the desired cellular potency characterizing high quality chemical probes, the correlated antiproliferative phenotype and the favorable in vitro selectivity profile suggest that further optimization of this scaffold could potentially lead to valuable tools for interrogating KDM5 phenotypes in human biology.

DTP3 is a D-tripeptide with a molecular weight of 525 Da, which retained all the main characteristics of the parental D-tetrapeptides in terms of bioactivity and specificity, including subnanomolar activity and high stability in vitro and potent and selective capacity to kill MM cells via apoptosis. DTP3 is a selective MKK7 binder, driving to a sustained JNK activation and consequent death of MM cell lines expressing GADD45β. DTP3 is about to enter clinical studies as a potential treatment for multiple myeloma.

SRT1720 is a small-molecule compound, which has the ability of activating the sirtuin subtype SIRT1. It’s not a direct activation. SRT1720 exhibits multiple off-target activities against receptors, enzymes, transporters, and ion channels. SRT1720 affects mitochondrial respiration in a Sirt1- and PGC-1α-dependent manner. SRT1720 has been demonstrated to enhance insulin sensitivity and improve measures of mitochondrial capacity and oxidative metabolism. SRT1720 also significantly inhibits VEGF-dependent multiple myeloma cell migration. SRT1720 is an experimental drug that was studied by Sirtris Pharmaceuticals. At 2013 year, GlaxoSmithKline was closed down Cambridge, MA-based Sirtris Pharmaceuticals.

NVP-ADW742 is a novel small weight molecular inhibitor of insulin-like growth factor-1 receptor (IGF-IR), which is investigated for treatment of different types of cancers.

AEW-541 is a pyrrolo[2,3-d]pyrimidine derivative small molecular weight kinase inhibitor of the IGF-IR IGF-1R/InsR with IC50 of 150 nM/140 nM in cell-free assays, greater potency and selectivity for IGF-1R in a cell-based assay. In vivo, this orally bioavailable compound inhibits IGF-IR signaling in tumor xenografts and significantly reduces the growth of IGF-IR-driven fibrosarcomas. AEW-541 represents a class of selective, small molecule IGF-IR kinase inhibitors with proven in vivo antitumor activity and potential therapeutic application.

Tubacin is a highly potent and selective, reversible, cell-permeable inhibitor of HDAC6 with an IC50 value of 4 nM. Tubacin inhibits α- tubulin deacetylation in mammalian cells. Tubacin is specific for the tubulin deacetylase activity of HDAC6. The effects of tubacin has been studied in hematologic malignancies, such as multiple myeloma and leukemia cell lines. Overexpression of HDAC6 in primary lymphocytes and T cell lines increase cell migration in response to cytokines. Knockdown of HDAC6 in T cells decreased chemotactic mobility independent of its enzymatic activity. Furthermore, treatment of multiple myeloma cells with tubacin resulted in decreased cell growth at an IC50 of 2–5uM. In terms of toxicity to normal bone marrow and blood cells, treatment of peripheral blood mononuclear cells (PBMC) and bone marrow progenitor cells (BMPC) with tubacin (5uM) for 12 hours showed that constitutive expression of HDAC6 is higher in BMPCs than PBMCs. Furthermore, acetylation of α-tubulin was markedly enhanced by tubacin in BMPCs but not in PBMCs. Bortezomib and tubacin together induced synergistic antitumor activity in multiple myeloma cells and primary bone marrow plasma cells. Published data therefore provide support for combined therapy in clinical trials for patients with multiple myeloma.

PK-11195 was first discovered by Pharmuka Laboratories. It was found to be antagonist of the Translocator Protein (TSPO) with potential for development in a number of conditions including cancer models, cardiac ischemia, seizures, depression, and anxiety. PK-11195 has been studied extensively in vitro and in animal models. In phase I clinical trials no anti-inchemic effects were found after drug administration. A tritium [3H] labeled and a C-11 labeled version of PK-11195 are both used diagnostically as PET imaging compounds.