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On April 6, Incyte announced a key phase III ECHO – 301 (KEYNOTE – 252) the results of clinical research, according to data epacadostat inhibitor (IDO) joint Keytruda inhibitors (PD – 1) treatment is surgical resection or metastatic melanoma than used alone Keytruda failed to significantly improve progression-free surial (PFS). It marked the loss of epacadostat in the field of melanoma, and Incyte lost more than 20% of its market value on that day.

The result may be a cautionary tale about overheating IDO inhibitors, but should not be overly pessimistic in the field of drug research. So-called CheDuanCunChang, even Keytruda and Opdivo have encountered clinical fail, so it is not necessary to kill a great IDO inhibitors, or completely deny the development direction of small molecular tumor immunotherapy.

On April 2-6, the 13th annual conference on drug development and chemistry was held in San Diego, United States, to see what progress has been made in the field of immunotherapy for small molecular tumors reported at the conference.

Immunotherapy of targeted tumor microenvironment.

Immunosuppressive Treg and MDSC in tumor microenvironment were associated with poor prognosis. Suppressing Treg or causing Treg damage is a potentially attractive cancer immunotherapy. In tumor microenvironment, Foxp3 +Treg can be highly immunosuppressed, which limits the anti-tumor response of Teff cells, such as CD8 +T cells, thereby promoting the growth and development of tumors. Tip60 is a histone acetyltransferase, which plays a leading role in promoting the acetylation, polymerization and function of Foxp3 in Treg. To ubiquitin enzyme USP7 belongs to cysteine protease, is one of the important members of ubiquitin specific protease family, involved in cell survival and cell cycle regulation, chromosome recombination, multiple signaling pathways that control. USP7 can affect the Treg function by adjusting the Foxp3 and Tip60.

Progenra company focused on targeting the ubiquitin-proteasome pathway and related protein modification system of drug discovery, is using its UbiPro ™ drug discovery platform of the ubiquitin-proteasome pathway of several molecular targets for drug research of tumor, including to ubiquitin enzymes (DUBs) and ubiquitin E3 ligase. At present, Progenra has developed an effective USP7 inhibitor, which effectively attenuates the Treg immunosuppression function in multiple homologous solid tumor models. Using the USP7 inhibitor alone or in combination can increase the effectiveness of cancer immunotherapy and expand its therapeutic range.

“The data we obtained later showed that our USP7 inhibitors have the potential to eliminate cancer through direct cytotoxicity and indirect immune mechanisms. Such drugs could be a powerful alternative to current market bioimmunocheckpoint inhibitors (such as Opdivo and Keytruda) and as an integral part of their combined treatment with these drugs. Dr. Tauseef Butt, President of Progenra, said he hopes to begin research on the USP7 inhibitor early in 2018. Left is the ubiquitin-proteasome pathway and inhibitor illustrated below, inhibitors of drug lenalidomide, mooring horse degrees of amine, ora panitan stars such as drugs, r for Progenra companies related to ubiquitin disclosed in the patent document inhibitors structure chart.

A DRD2 antagonist that stimulates the activity of immune stimulation.

The G protein coupled receptor (GPCRs) is the largest receptor family on the surface of human cells. These complex receptors regulate the important physiological functions by binding to the extracellular ligands and controlling many signal transduction pathways in the cell. Due to the diversity of this receptor family and its control of the large signal pathways, GPCRs usually disorders in human disease, more than a third of the listed drugs targeting one or more of these receptors.

Imipridones are an anticancer compound developed by Onipceutics, which can selectively target GPCRs. The first imipridone skeleton compound in the clinical stage is ONC201, which can specifically antagonistic immune cell expression of DRD2. ONC201 showed immune-stimulating effect in preclinical studies, including increased infiltration of NK cells in xenograft. Consistent with the clinical observation before, in prostate cancer, endometrial cancer, glioblastoma and cell lymphoma patients observed circulation and NK cells within the tumor, an increase in cytokines and effector molecule. In the clinical study, it also showed good tolerability and therapeutic effect, no SAE related to toxicity or cessation of treatment due to toxicity, median OS was 41.6 weeks, OS6 was 71%, and OS9 was 53%.

Tlr7/8 agonist for cancer immunotherapy.

Cytotoxic T lymphocytes (CTLS) play a major role in cancer immunotherapy because they can directly kill tumor cells and secrete tumor suppressor cytokines. The anticancer vaccine is designed to stimulate tumor-specific CTL responses, which require the activation of antigen presenting cells (apcs), including dendritic cells (DC) and macrophages. Therefore, the strong immune stimulation adjuvant that can activate APC is an important part of the anticancer vaccine. Toll-like receptors (TLRs) is used as a vaccine adjuvant and design key targets for anticancer treatment of immune modulators, TLR7 and TLR8 in activated natural and acquired immune response plays an important role, almost on the all kinds of cells involved in antitumor immune response are activated.

Dr John Vasilakos of 3M drug delivery systems and David Ferguson of the university of Minnesota presented their respective tlr7/8 agrochemicals at the conference. Professor David Ferguson of the university of Minnesota focused on design synthesis and studied the use of tlr7/8 agonist as an immune-stimulating adjuvant. And 3 m company has related TLRs agonist products listed, in the first TLR7 agonist Aldara listed after 3 m synthesized more than 10000 different molecules, can be used as a selective TLR7, selective TLR8 or TLR7/8 agonist, the agonist indications for a variety of skin diseases have potential effect. At present, Medimmune has obtained the research license of 3M-052 (MEDI9197), and cooperated with astrazeneca in the joint use of imfinzi to treat the clinical study of solid tumors.

It is worth noting that Nitor Therapeutics reported a purine nucleoside phosphorylase (PNP) inhibitors as the role of immune enhancer, represent a new class of small molecule immune therapy for oral bioavailable. PNP inhibitors activate the immune system by regulating endogenous metabolites to enhance the immunotherapy effect of cancer. In addition to the secondary, there are also the at-s-977 targeted to regulate mitochondrial function to promote the immune response of cancer, and the large ring non-peptide compounds, ca-170 and AX101, which are targeted to pd-1 /L1, are no longer detailed.

It can be seen that small molecular compounds, as immunotherapy for cancer, still have more research content and application methods, and should not be a hero with the success or failure of a drug. Relatively small drug molecules in biological immune therapy, there are still a lot of advantages, such as: oral bioavailability, targeting the tumor microenvironment, as well as the advantage in cost and application, etc., the most important thing is that should take advantage of small molecule drugs and biological antibody of their respective advantages, fully exert effective means for the treatment of cancer.

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