In addition to the T-cell Lymphoma,T-cell Acute Lymphoblastic Leukaemia mentioned in our previous article, there are also related studies of protac in other blood diseases. Next, let’s analyze the research of protac in Acute Myeloid Leukemia and B cell lymphoma.
Research of Protac on Acute Myeloid Leukemia
Mouse microsomal 2 homologue (MDM2) is an E3 ubiquitin ligase, which can promote the degradation of p53 tumor suppressor gene. TP53 gene mutations in many tumors do not bind to MDM2. Nevertheless, MDM2 has become a target for wild-type cancer therapy in TP53. Although the incidence of TP53 gene mutation in AML is very low (15-20%), overexpressed MDM2 can reverse regulate wild-type p53 protein and inactivate it. Therefore, MDM2 is an attractive target for the new therapy of AML, which is specifically used to treat MDM2 overexpression but TP53 wild type AML.
Several MDM2 inhibitors are currently in clinical trials. However, p53 stabilization upregulates MDM2, thus limiting the clinical efficacy of inhibitors. PROTAC molecules recruit target proteins for degradation, so the efficiency can be improved by removing the target proteins.
The team at the University of Michigan Cancer Center developed a MDM2 PROTAC degrader, MI-265, which binds to MDM2 and targets it to degrade, eliminating the inhibitory effect of p53 and inducing apoptosis in leukemic cells. The researchers collected 96 samples from primary acute myeloid leukemia to detect MI-265. It was found that the sensitivity and drug resistance of most samples to MDM2 degraders and inhibitors were similar, indicating that the action mechanisms of the two drugs were also similar.
In addition, the treatment of normal CD34 positive hematopoietic cells in apoptosis test and colony formation test showed no toxicity to normal hematopoiesis. MI-265 is a highly effective MDM2 degrader and is currently undergoing extensive preclinical evaluation for the treatment of acute leukemia.
In summary, MI-265 is a highly effective MDM2 degrader and is currently undergoing extensive preclinical evaluation for the treatment of acute leukemia.
Research of Protac on B cell lymphoma
MALT1 is a protease and scaffold protein that participates in the downstream of B cell (BCR) and T cell receptor (TCR) signal transduction, NF-κB. MALT1 is abnormally activated by upstream gene (CD79A/B, CARD11, MYD88) mutations of BCR and TLR pathway in ABC-DLBCL, which is essential for proliferation and survival.
Recent studies have found that MALT1 protease activity indicates that MALT1 has therapeutic targeting in ABC-DLBCL. MALT1 is also necessary for CLL, MCL and some solid tumors, especially lung cancer and glioblastoma.
Recently, a first clinical trial in humans has begun to evaluate the role of MALT1 protease inhibitor in non-Hodgkin’s B-cell lymphoma. However, in the protease inactivated mouse model, chronic inactivation of MALT1 protease inhibits T regulatory cells in the body, leading to rapidly progressive autoimmune disease and death.
On the other hand, the loss of MALT1 also has an effective anti-tumor effect, but does not lead to autoimmunity in mice. These findings prompt us to study alternative MALT1 targeted therapy for its stent activity. The research team at will Cornell Medical School developed a series of PROTAC for MALT1. These MALT1 PROTACs are based on allosteric MALT1 inhibitors, which reversibly bind to MALT1 and partially fuse with glutenin (CRBN) to bring the CRBN E3 ligase complex close to MALT1 and promote its ubiquitin and proteasome degradation.
The researchers analyzed the structure-activity relationship of the constructed PROTACs and evaluated the MALT1 enzyme inhibitory activity of three binding sites of MALT1, and the effects of different length and polarity of binding sites on the degradation of MALT1, and compared the affinity of Lenalidomide, Pomalidomide and CC-220 as linker with CRBN.
Through a series of screening tests, the researchers finally selected the two most effective and selective compounds to verify the action mechanism of MALT1-PROTACs. Different from the parent MALT1 targeting allosteric compounds, MALT1 PROTACs degrades MALT1 effectively in a CRBN-dependent manner.
In addition, unlike MALT1 protease inhibitors, MALT1 PROTACs can effectively inhibit the activation of NF-κB, which is dependent on the activity of MALT1 stents.
In summary, the data suggest that MALT1 PROTACs may be an excellent drug for the treatment of ABC-DLBCL and other lymphomas, providing an alternative to enzyme-targeted therapy, which may help to avoid autoimmunity or overcome the mechanism of drug resistance.