Oral presentation features structural disclosure and preclinical characterization NX-2127, Nurix’s lead BTK degrading agent for the treatment of B-cell malignancies
The poster presentation highlighted the specificity and potency of NX-5948 and the superior cellular activity against BTKi resistance mutations of both NX-2127 and NX-5948 compared to others. Published BTK Degrader
SAN FRANCISCO, April 17, 2023 (GLOBE NEWSWIRE) — Nurix Therapeutics, Inc. (Nasdaq: NRIX) announces a clinical-stage development of targeted protein modulators designed to treat patients with hematologic malignancies and solid tumors. A biopharmaceutical company and, today, a targeted protein degradation program that includes structural disclosure of NX-2127 and new preclinical data for NX-2127 and NX-5948. B-cell malignancy. These data will be presented at the American Association for Cancer Research (AACR) Annual Meeting, April 14-19, 2023 in Orlando, Florida.
President and Chief Executive Officer Arthur T. Sands, M.D., said: of Nurix. “Nurix represents an excellent class of targets with broad potency against wild-type BTK and all mutations tested to date, with the potential to provide novel therapeutics for patients for whom there are no existing options. Leading the field in developing proteolytic drug candidates. Failed.”
AACR presentation details
in a poster presentation titled NX-5948 selectively promotes subnanomolar degradation of inhibitor-resistant BTK mutants. Preclinical data demonstrating potent tumor cell killing activity of Nurix’s BTK degradants (NX-5948 and NX-2127) against a wide range of acquired BTK inhibitor resistance mutations and their superiority compared to other reported degradants was presented. Specifically, NX-5948 was shown to target and promote potent degradation of V416L, T474I, and L528W BTKi resistance mutations that reduce or eliminate the activity of next-generation noncovalent BTK inhibitors such as pirtbrutinib. it was done. The broad-spectrum activity of NX-2127 and NX-5948 against BTK mutations, compared to BTK inhibitors and other BTK-degrading agents, adds additional mechanisms to ongoing clinical trials in patients with advanced B-cell malignancies. provide rationale.
“Presentation at the AACR and ACS conferences demonstrates Nurix’s approach of combining a deep understanding of the biochemistry of E3 ligases and the pharmacodynamics of target proteases with the principles of rational drug design,” said Dr. Gwenn Hansen. said. , Chief Scientific Officer of Nurix. “With our unique drug discovery expertise, we have the potential to design targeted protein modulators that can address one or more important therapeutic targets and combine their activities into a single molecule that may benefit specific diseases. I have.”
The mechanistic basis for overcoming mutation resistance is that NX-5948 cooperatively binds to BTK and the E3 ligase cereblon and maintains a stable ternary complex despite reduced binding affinity to the mutant and is supported by data showing that it can retain degradative activity against specific BTKi resistance mutations. BTK protein. BTK degradation by NX-5948 was shown to be highly selective in proteomic assessments, with significant off-target activity observed in primary T cells, TMD8 cells, or MM-1R cells treated with NX-5948. did not.
In an oral presentation entitled First Disclosure of NX-2127, an Oral Targeted Degradation Agent of Bruton’s Tyrosine Kinase (BTK) with Concomitant Immunomodulatory Activity for the Treatment of B Cell MalignanciesThe structure of NX-2127 was disclosed to a broader oncology audience at AACR following initial disclosure in an oral presentation at the American Chemical Society Spring Meeting on March 29, 2023. The presentation also included preclinical characterization and early pharmacokinetic and pharmacodynamic data. in humans.
Registered attendees will be able to view all presentations and posters on demand on the AACR website. Nurix’s AACR presentation is also available in the posters and presentations section of the Scientific Resources page of the Nurix website.
NX-2127 is a novel bifunctional molecule that degrades Bruton’s tyrosine kinase (BTK) and the cerebroneogenic substrates Icarus (IKZF1) and Aeolus (IKZF3). NX-2127 is currently being evaluated in Phase 1 clinical trials in patients with relapsed or refractory B-cell malignancies. Additional information about ongoing clinical trials can be accessed at www.clinicaltrials.gov (NCT04830137).
NX-5948 is an investigational, orally bioavailable, small-molecule degrader of BTK that, unlike NX-2127, is designed as a single-targeted degrader. NX-5948 is currently being evaluated in a Phase 1 clinical trial in patients with relapsed or refractory B-cell malignancies. Additional information about ongoing clinical trials can be accessed at clinicaltrials.gov (NCT05131022).
About Nurix Therapeutics, Inc.
Nurix Therapeutics is a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of small molecules and cell therapies based on modulation of cellular protein levels as novel therapeutic approaches for cancer and other challenging diseases. Nurix will leverage its extensive expertise in E3 ligases and proprietary DNA-encoded libraries to identify and advance drug candidates that target E3 ligases, a broad class of enzymes that can regulate proteins within cells. built DELigase, an integrated discovery platform for Nurix’s drug discovery approach is to exploit or inhibit the natural function of E3 ligases within the ubiquitin proteasome system to selectively decrease or increase cellular protein levels. Nurix’s wholly-owned pipeline includes a targeted proteolytic agent for Bruton’s tyrosine kinase, a B-cell signaling protein, and inhibition of Casitas B-lineage lymphoma proto-oncogene B, an E3 ligase that regulates T-cell activation Includes drug. Nurix is headquartered in San Francisco, California. For more information, see:
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Dr. Elizabeth Wolfe
Wheelhouse Life Science Advisor
Wheelhouse Life Science Advisor