KTX-120: Targeting MYD88-Mutant DLBCL with Selective IRAK4 and IMiD Substrate Degradation for Tumor Regression

The objective of cancer treatment is to enhance patient outcomes by eliciting profound and lasting responses against tumors. The efficacy of single-agent drugs like BTK inhibitors or IMiDs has been limited in relapsed and resistant cases of diffuse large B-cell lymphoma (DLBCL), leading to the need for combination therapies. Targeted protein degraders are small molecules that utilize the body's own ubiquitin-proteasome system to selectively degrade specific proteins. IRAK4 degraders, which target a critical component of the myddosome complex, have shown to be effective in MYD88-mutant DLBCL models, with degradation being more effective than kinase inhibition.

IRAKIMiDs are a new type of IRAK4 degraders that use an IMiD to bind cereblon, leading to the simultaneous degradation of IRAK4 and IMiD substrates. These degraders have shown to have a synergistic effect against tumors, combining therapeutic benefits within a single molecule.

KTX-120 is a new IRAKIMiD candidate that effectively degrades both IRAK4 and IMiD substrates in lymphoma models with low nanomolar DC50 values. Its activity is highly dependent on the MYD88 mutation status, with potent effects in MYD88-mutant cell lines and poor activity in wild-type lines. KTX-120's rapid onset of cell death suggests that continuous exposure may not be required for its antitumor effect.

In vivo studies have shown that KTX-120 is orally bioavailable and exhibits dose-dependent exposure. It has demonstrated significant degradation of IRAK4 and Ikaros substrates in a sustained manner, supporting the possibility of intermittent dosing. KTX-120 has shown potent antitumor activity in MYD88-mutant DLBCL models with well-tolerated intermittent dosing schedules.

Furthermore, KTX-120 has shown robust activity in a majority of MYD88-mutant DLBCL patient-derived xenograft models, regardless of other mutations that activate the NFkB pathway. This indicates that KTX-120 could be effective in MYD88-mutant lymphoma with various co-mutations.

Overall, the data indicates that KTX-120's dual action of IRAK4 degradation and IMiD activity could lead to significant and lasting tumor regressions in MYD88-mutant lymphomas, offering the advantage of a single agent administered intermittently and reducing the complexity of drug combination challenges.