MD Anderson Cancer Center
Project Term: July 1, 2023 - June 30, 2026
Most patients respond well to drugs that inhibit an important MCL target named BTK. However, almost all of them will eventually relapse and then do very poorly. Inhibition of MALT1, a target which is biochemically downstream of BTK, may rescue many of these patients, and inhibiting both BTK and MALT1 may be better still. Developing a drug that inhibits both targets at the same time, from the beginning of treatment, will avoid some complications and likely be best of all; we will find out.
Fortunately, quite a few therapies have been developed in recent years that substantially improve survival and quality of life for most patients with MCL. An excellent example of this is ibrutinib, which inhibits a protein called BTK that has become overactive. In a clinical trial led by Dr. Wang, ibrutinib performed so well that it quickly gained FDA approval in 2013 and is still very frequently used. Unfortunately, ibrutinib responsiveness almost invariably relapses eventually. Other BTK inhibitors were developed with different characteristics; one of them, pirtobrutinib, not only somewhat outperformed ibrutinib but also produced responses in many patients who had relapsed on ibrutinib. Nonetheless, patients treated with pirtobrutinib (or any other therapy) are still vulnerable to relapse. We discovered that many patients who relapsed on BTK inhibitors showed hyperactivity of another protein, MALT1, that is biochemically downstream of BTK. In consequence, BTK is bypassed whether or not the inhibitor was still able to bind to it, and the signaling pathway remains overactive. Again fortunately, MALT1 can be effectively inhibited by the drug safimaltib. We have also discovered that simultaneous targeting of BTK with pirtobrutinib and MALT1 with safimaltib works better than either inhibitor alone in animal models. Using two drugs together is not uncommon, but there are downsides that increasingly encourage the development of dual-targeted drugs; in our case, that would be a single drug that inhibited both BTK and MALT1. We began investigating how to make a drug that bound to BTK in the same way as pirtobrutinib and to MALT1 in the same way as safimaltib, and have already had some success, with one compound being superior to pirtobrutinib and safimaltib whether they were used singly or together. In this project, we will synthesize additional candidates, assess their long-term effectiveness, stability, and safety, and determine their mechanisms of action. We anticipate that the best of our developed agents would be eligible for clinical testing and then patient use.