Study On The Structure-activity Relationships Of MI-2 Analogues As MALT1 Inhibitors

Lymphoma is a heterogeneous group of hematological malignancies.Diffuse large B cell lymphoma(DLBCL)is the most common subtype,accounting for 30%-40%of all lymphoma cases.Novel structural drugs are urgently needed to improve the current therapy of ABC-DLBCLs,which are the most chemoresistant.Recent studies revealed that MALT1 is a promising therapeutic target for the treatment of ABC-DLBCL.Among several reported MALT1 inhibitors,small molecule MI-2 as an irreversible inhibitor has been widly studied in the preliminary mechanism of lymphoma.MI-2 as a lead compound with potential cross-reactivity need further chemical optimization.In this dissertation,a systemic structure-activity relationship(SAR)has been studied.Meanwhile,a bifunctional chimeric molecule targeting MALT1 degradation has been designed and synthesized.It includes two parts:Part 1:The SAR of MI-2.We have designed different expedient routes and synthesized more than 70 derivatives,focusing on modifications to five moieties within the skeleton of MI-2.Through the antitumor activity screening of focused compounds libraries in vitro,and some of biological mechanisms studies,the SARs of MI-2 were systematically and comprehensively summarized.All compounds were tested for the activity against DLBCL cell line in vitro.The systemic SARs revealed that both sites A and B are essential fragments to maintain the inhibitory potency,while changing site C might slightly decrease the activity.In addition,the side chain of 2-methoxyethoxy is more flexible and can be replaced by many functionalized groups,suggesting that MI-2 can assembly combine with other drugs via different linker to produce new compounds with more potent pharmacological effects.Furthermore,MI-2 analogues with terminal hydroxyl moiety on site D exhibit better inhibitory activity against MALT1.While,replacement of triazole core with pyrazole moiety is also tolerated,indicating that this core need more chemical modifications.Part 2:The PROTAC and its application in the treatment of lymphoma.Through the systemic SAR studies,we find that the site D of MI-2 is flexible and can be linked with other drug-like fragements to form novel lead compound.In this dissertation,a new approach has been developed to target MALT1 for protein degradation based upon the proteolysis targeting chimera(PROTAC)concept.The heterobifunctional molecule(4-12)is composed of three components:a ligand for the target MALT 1(MI-2 scaffold),an E3 ligase recognition motif(phthalimide moiety,such as thalidomide derivatives),and a linker(polyethylene glycol chain)that holds these two moieties together.The biological evaluation of this compound is still under investigation.