Full Press Release Details
NX-2127, a Degrader of BTK and IMiD
Neosubstrates, for the Treatment of B-Cell Malignancies Presenter: Daniel Robbins, Ph. D. drobbins@nurixtx.com Exhibit 99.1
Disclosures All authors of this
NX-2127 has a dual degradation
malignancies Mutations to BTK have conferred resistance to approved agents indicating an area of unmet medical need IMiD therapies have shown efficacy in some aggressive B-cell malignancies The dual action of BTK degradation and IMiD activity may
provide a unique treatment strategy for relapsed/refractory B-cell malignancies NX-2127 is a novel, hetero-bifunctional, orally administered, Chimeric Targeting Molecule (CTM) that induces the degradation of Bruton's Tyrosine Kinase (BTK) in
cells through recruitment of cereblon (CRBN), a component of the CRL4-CRBN ubiquitin ligase complex The engagement of NX-2127 also catalyzes neosubstrate degradation of Aiolos (IKZF3) and Ikaros (IKZF1), two transcription factors regulating T-cell
function Harness (CRBN binder) Hook (BTK binder) Linker NX-2127 Ubiquitin BTK CRBN Catalytic ubiquitination Proteasome BTK A B CRBN BTK Degradation Ikaros Aiolos Catalytic ubiquitination Degradation Proteasome CRBN ubiquitin ligase complex CRBN
ubiquitin ligase complex
NX-2127 catalyzes BTK degradation and
BTK degradation in Rec-1 and Mino mantle cell lymphoma cell lines NX-2127 potently blocks cell proliferation of BTKC481S TMD8 cells relative to ibrutinib DC50 = half maximal degradation concentration HTRF = Homogeneous Time Resolved Fluorescence A B
NX-2127 has minimal in vitro effects on
NX-2127 catalyzes Aiolos degradation
to that of pomalidomide and lenalidomide NX-2127 exhibits IMiD-like activity by activation and IL-2 production following CD3/CD28 stimulation
Oral Administration of NX-2127
Ibrutinib-Resistant Lymphoma NX-2127 demonstrates comparable tumor growth inhibition to ibrutinib in a xenograft mouse model containing tumors with a wild type BTK NX-2127 shows more potent tumor growth inhibition compared to ibrutinib in a
xenograft mouse model containing tumors with the most common human resistance mutation (C481S) in BTK target protein
Oral Dosing of NX-2127 Degrades BTK in
daily, oral dosing of NX-2127 maintains suppression of BTK protein levels throughout the 19-day duration of the study (NX-2127 PK t1/2 = 5.4 h) QD QD QD
Summary and Conclusions NX-2127
catalyzes potent BTK degradation in vitro and results in anti-proliferative effects in human lymphoma cell lines The IMiD activity of NX-2127 is similar to that of IMiD drugs pomalidomide and lenalidomide and results in T-cell activation NX-2127
demonstrates potent BTK degradation in vivo upon oral dosing in cynomolgus monkey and displays anti-tumor effects in both wild-type and C481S mutant mouse xenograft tumor models NX-2127 combines BTK degradation with IMiD activity to provide an
Acknowledgements Chemistry Daisuke
Kato Zef Konst Jose Leighton Oliver McConnell Joel McIntosh Ge Peng Josh Taygerly Jeffrey Wu Jeff Mihalic Christoph Zapf Development Timothy Ingallinera Janine Powers Jenny McKinnell Dane Karr Drug Discovery Technologies Eileen Ambing Andrew
Sawayama Naimee Mehta Herman Yuen Paul Novick Jose Santos Dahlia Weiss Mario Cardozo Matt Clifton Stefan Gajewski Collaborators NIH NHLBI Adrian Wiestner Sarah Herman Hailey Harris Deyi Zhang Tokyo Medical and Dental University (TMD8 cells) Biology
& Lead Discovery Jordan Ye Mark Noviski Austin Tenn-McClellan Szerenke Kiss von Soly Jennifa Gosling Karl Doerner Stephanie Yung Kathleen Boyle Diana Mu oz Steve Basham Preclinical Pharmacology May Tan Anna Kolobova Luz Perez Jennifer Tung
Ryan Rountree Jennie Stokes Sasha Borodovsky Project Leadership & Project Management Aileen Kelly Dan Robbins Elsa Tretter Nurix Leadership Arthur Sands Pierre Beaurang Robert Brown Hans Van Houte Cristiana Guiducci Gwenn Hansen Howard Simon