New Angle Upon small molecule libraries faah inhibitor Just Unveiled

ding BCL. AntiCD20 faah inhibitor antibodyCpGconjugates have been shown to eradicate rituximabresistantBCL in a syngeneic murine lymphoma model. A recent demonstrationof the divergent effects of CpG ODNs on normalversus malignant B cells might suggest a novel mechanismof action for CpG ODNs as therapeutic agents for BCL.5.9. Heat Shock Proteins. Hsps are chaperonesneeded for the right functioning of proteins involvedin cell growth and survival. Inhibition of these proteinsresults in improved degradation of key proteins such askinases, signal transducer proteins, and mutated oncogenicproteins. GUT70, a tricyclic coumarin derived from Calophyllumbrasiliense, has shown pronounced antiproliferativeeffects in MCL withmutanttype p53, a known negativeprognostic aspect for MCL, via Hsp90 inhibition.
These findings suggest that GUT70 could possibly be potentiallyuseful for the treatment of MCL.The smallmolecule 17AAGcan induce cell death in a doseand timedependentmanner by lowering the cellular contents faah inhibitor of criticalsurvival proteins, which includes Akt and cyclin D1 in a rangeof lymphoma cell lines. Various clinical responses wereobserved in a phase II study of 17AAG in individuals withRR MCL or HL. SNX2112 was found to exert effects incombination with bortezomib and rituximab in rituximabresistantNHL cell lines. SNX2112 is presently in phaseI clinical trials.5.10. Angiogenesis. Tumor angiogenesis is importantin many different hematologic malignancies. Bevacizumab,already small molecule libraries extensively studied in solid tumors, has alsobeen evaluated in lymphoma.
In a phase II SWOG study of RCHOPplus bevacizumab in individuals with advanced DLBCL,the observed 1year PFS estimate trended higher than thehistorical estimate. Nevertheless, as considerable toxicities wereassociated with all the addition of bevacizumab the regimen wasnot suggested for further evaluation. In a phase IIstudy NSCLC of singleagent sunitinib in RR DLBCL, no evidence ofactivity was recorded and hematologic toxicities had been greaterthan anticipated. The vascularendothelialgrowthfactor12 fusion protein, aflibercept, has beenevaluated in a phase I study in combination with RCHOPin untreated individuals with BCLs. The 6 mgkg doseof aflibercept is utilized in all ongoing phase III trials in otherindications, and the combination with RCHOP resulted inhigh response rates in this study. The primary grade 3 or 4adverse events integrated hypertension, febrile neutropenia, and asthenia.
Preliminary results are readily available from 2 recent phase IItrials with sorafenib. In a singleagent study in heavily small molecule libraries pretreatedpatients with RR NHL, numerous responses werenoted and therapy was overall well tolerated. In a phaseII study in combination with all the Akt inhibitor perifosinein RR lymphomas, numerous PRs had been observed, withthrombocytopeniathe most common drugrelatedhematological toxicity. A phase II study in recurrentDLBCL is presently ongoing. The combinationof sorafenib and everolimus was shown to be welltolerated, with activity observed, specifically in HL, in a phaseI trial in individuals with lymphoma or MM.5.11. Further Targeted Agents and Novel Therapeutics.Farnesyltransferases are key cellular enzymes involved in theprenylation of proteins.
Prenylated proteins are importantfor malignant cell growth. The oral farnesyltransferaseinhibitor, faah inhibitor tipifarnib, has been assessed in a phase II study inpatients with relapsed, aggressive, indolent, or uncommonlymphoma. Tipifarnib had a superb tolerability profile anddemonstrated activity in lymphoma, with responses inpatients with heavily pretreated DLBCL, HL, and Tcelltypes, despite the fact that little activity was observed in follicular NHL.MLN4924 is an investigational inhibitor of Nedd8activatingenzyme, which plays a essential role in regulatingthe activity from the cullinRING E3 ligases.Preclinical activity has been demonstrated in a novel primaryhuman DLBCL xenograft modeland a phase 1 doseescalationstudy of several dosing schedules is currentlyunderway in individuals with RR MM or lymphoma.
Potential molecular targets for novel therapeuticsare beginning small molecule libraries to be identified via anemerging area in lymphoma biology involving energy metabolism.Personalized medicine approaches using bifunctionalimaging and therapeutic agents are based on the premisethat glucose metabolism rates are high in aggressive Bcelllymphomas. Use of this bifunctional pathway as atargeted therapy has been explored lately with 187rheniumethylenedicysteineNacetylglucosamine, a synthetic glucoseanalog, which accumulates in cancer cell nuclei and invarious tumors in animal models. Biodistribution data revealedthat radioactivity was retained in tumor tissue 2 hoursafter injection with little uptake in the plasma when comparedwith tumor tissue. The compound was excreted overa longer incubation period, and the retention time in lymphomatissue was longer than that of other tissues. Theresults suggest that the metallic pharmaceutical agent 187ReECG might be a potential candidate for targeted therapy inaggressive RR lymphomas.The lately developed, smallmolecule