Protein degrader overcomes resistance in B-cell malignancies

Blood cancer

A paper in the journal Science has identified a new class of BTK mutations that are susceptible to NX-2127, a novel BTK and IKZF1/3 degrader. 

The study ‘Kinase Impaired BTK Mutations Are Susceptible to Clinical Stage BTK and IKZF1/3 Degrader NX-2127’ elucidates a previously unappreciated oncogenic scaffold function of BTK responsible for clinical resistance to enzymatic inhibitors.

It goes on to show that NX-2127, a potent targeted protein degrader with differentiated activity against BTK and IKZF1/3, can overcome this resistance across a broad range of acquired mutations.

“While BTK inhibitors have positively changed clinical outcomes for patients with B-cell malignancies, the emergence of acquired resistance to these medicines is a growing clinical problem,” said Alexey Danilov, Professor and Co-Director, Toni Stephenson Lymphoma Center, City of Hope National Medical Center.

“Identification of the different types of mutations has important implications for the therapeutic sequencing of currently used targeted BTK inhibitors and reinforces the need for the development of novel agents, such as Nurix’s NX-2127 and NX-5948, that have the potential to provide improved mutation-agnostic treatment options for patients.”

A novel mechanism of action

The article describes studies designed to investigate and characterise acquired BTK mutations that confer resistance to BTK inhibitors commonly used in the treatment of B-cell malignancies.

The research identified a new class of kinase impaired mutants that render BTK enzymatically inactive and revealed that these mutations create novel protein-protein interactions that can propagate biochemical signalling through a process known as scaffolding, a nonenzymatic function of the BTK protein that sustains B-cell receptor (BCR) signalling and promotes the growth of malignant B-cells.

Importantly, the authors report data demonstrating efficient proteasomal degradation of BTK in the blood of all NX-2127-treated patients with chronic lymphocytic leukaemia (CLL), resulting in reduction of BTK enzymatic activity and suppression of BCR signalling regardless of mutational status.

The work was carried out by Nurix Therapeutics in collaboration with scientists and clinicians at several prominent cancer research centres, including Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine and the Sloan Kettering Institute at Memorial Sloan Kettering Cancer Center.

“These publications represent the first compendium of biochemical, cellular and clinical evidence that NX-2127 degrades both previously described and newly discovered BTK inhibitor resistance mutations, a novel mechanism of action in the treatment of B-cell malignancies that is associated with meaningful clinical responses,” said Gwenn Hansen, Chief Scientific Officer of Nurix. “The data described in this publication in Science reinforce the broad utility of the targeted protein degradation mechanism compared to inhibition approaches to more completely block BTK function and potentially other important enzymatic disease targets where development of acquired resistance is an issue.”

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