piperidines and pomalidomide

Novel insights into the pathophysiology of primary central nervous system lymphoma (PCNSL) have identified the B-cell receptor and Toll-like receptor pathway as well as immune evasion and suppressed tumor immune microenvironment as a key mechanism in the pathogenesis of PCNSL. Small molecules and novel agents targeting these aberrant pathways have been introduced into clinical trials targeting the recurrent or refractory PCNSL patient population. Agents like the Bruton tyrosine kinase (BTK) inhibitor ibrutinib or immunomodulatory drugs (IMiDs) like pomalidomide and lenalidomide have shown promising high response rates in the salvage setting. Here, we give an overview about the recent, exciting developments in PCNSL and summarize the results of clinical trials using novel agents in the recurrent and refractory salvage setting, which include immune checkpoint inhibitors, IMiDs, as well as BTK, phosphatidylinositol-3 kinase, and mammalian target of rapamycin inhibitors.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aminopyridines; Antineoplastic Agents, Immunological; Burkitt Lymphoma; Central Nervous System Neoplasms; Humans; Immunologic Factors; Lenalidomide; Lymphoma, Large B-Cell, Diffuse; Lymphoma, T-Cell; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Rituximab; Salvage Therapy; Thalidomide; Toll-Like Receptors; TOR Serine-Threonine Kinases; Tumor Escape

The incorporation of novel agents such as bortezomib and lenalidomide into initial therapy for multiple myeloma has improved the response rate of induction regimens. Also, these drugs are being increasingly used in the peri-transplant setting for transplant-eligible patients, and as part of consolidation and/or maintenance after front-line treatment, including in transplant-ineligible patients. Together, these and other strategies have contributed to a prolongation of progression-free survival (PFS) and overall survival (OS) in myeloma patients, and an increasing proportion are able to sustain a remission for many years. Despite these improvements, however, the vast majority of patients continue to suffer relapses, which suggests a prominent role for either primary, innate drug resistance, or secondary, acquired drug resistance. As a result, there remains a strong need to develop new proteasome inhibitors and immunomodulatory agents, as well as new drug classes, which would be effective in the relapsed and/or refractory setting, and overcome drug resistance. This review will focus on novel drugs that have reached phase III trials, including carfilzomib and pomalidomide, which have recently garnered regulatory approvals. In addition, agents that are in phase II or III, potentially registration-enabling trials will be described as well, to provide an overview of the possible landscape in the relapsed and/or refractory arena over the next 5 years.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Clinical Trials, Phase III as Topic; Disease-Free Survival; Drug Resistance, Neoplasm; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Immunologic Factors; Indoles; Multiple Myeloma; Oligopeptides; Panobinostat; Phosphorylcholine; Piperidines; Proteasome Inhibitors; Pyridines; Remission Induction; Thalidomide; Thiazoles; Treatment Outcome; Vorinostat

Protein tyrosine phosphatase SHP2 is a member of PTPs family associated with cancer such as leukemia, non-small cell lung cancer, breast cancer, and so on. SHP2 is a promising target for drug development, and consequently it is of great significance to develop SHP2 inhibitors. Herein, we report CRBN-recruiting PROTAC molecules targeting SHP2 by connecting pomalidomide with SHP099, an allosteric inhibitor of SHP2. Among them, SP4 significantly inhibited the growth of Hela cells, compared with SHP099, its activity increased 100 times. In addition, it can significantly induce SHP2 degradation and cell apoptosis. Further study of SHP2-protac may have important significance for the treatment of SHP2 related diseases.

Topics: Cell Cycle; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Molecular Docking Simulation; Molecular Structure; Piperidines; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Pyrimidines; Structure-Activity Relationship; Thalidomide

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Drug Resistance, Neoplasm; HEK293 Cells; HeLa Cells; Humans; Lymphoma, B-Cell; Mutation; Piperidines; Protein Domains; Proteolysis; Pyrazoles; Pyrimidines; Thalidomide