Biotheryx Presents Preclinical CDK4/6 and SOS1 Protein Degrader Data at AACR 2023 Annual Meeting
- Category: Small Molecules
- Published on Monday, 17 April 2023 16:57
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Data for CDK4/6 and SOS1 programs highlight differentiated therapeutic profiles
BTX-9341 nominated as development candidate for CDK4/6 degrader program for the treatment of solid tumors, currently in IND-enabling studies
SAN DIEGO, CA, USA I April 17, 2023 I Biotheryx, Inc., a biopharmaceutical company discovering and developing a portfolio of first-in-class protein degraders with a focus on validated targets in cancer and inflammatory disease, today announced data presentations on two first-in-class programs at the American Association for Cancer Research (AACR) 2023 Annual Meeting held in Orlando, Florida, on April 14–19, 2023. The presentations highlight preclinical data for bifunctional degraders of cyclin-dependent kinase (CDK) 4/6 for the treatment of solid tumors, and bifunctional degraders of son of sevenless homolog 1 (SOS1) for the treatment of KRAS mutant cancers. Additionally, the Company has nominated BTX-9341 as a development candidate for the CDK4/6 degrader program and has commenced IND-enabling studies.
"Biotheryx is advancing first-in-class bifunctional degraders developed through our PRODEGY platform to overcome common resistance mechanisms to existing inhibitors and provide differentiated treatment possibilities for people facing cancer," said Philippe Drouet, President and Chief Executive Officer of Biotheryx. "At AACR, we are proud to share encouraging preclinical data that highlights the potential of these exciting programs. BTX-9341, our oral CDK4/6 development candidate, has demonstrated superior efficacy in preclinical models of ER+/HER2- breast cancer when compared to CDK4/6 inhibitors, superior blood-brain-barrier penetration while importantly also showing the ability to be effective in models resistant to existing CDK4/6 inhibitors. Similarly, in preclinical KRAS mutant cancer models, our SOS1 degraders resulted in greater than 90% degradation of SOS1 in tumors and led to significant tumor growth inhibition."
AACR 2023 Presentation Details:
Title: Discovery of CDK4/6 bifunctional degraders for ER+/HER2- breast cancer and triple negative breast cancer
Presenter: Hannah Majeski, Ph.D., Principal Scientist - Biology
Abstract #: 1553
Session: Cell Cycle/Cell Proliferation Inhibitors for Cancer Therapy
Session Date and Time: Monday, April 17, 2023, at 9:00 a.m. ET
- CDK4/6 inhibitors are used to treat estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer, but some patients have exhibited innate resistance, and many are shown to develop acquired resistance after three years on therapy.
- Biotheryx's CDK4/6 bifunctional degraders demonstrated in vitro CDK4 and CDK6 degradation in multiple breast cancer cell lines and potent inhibition of cell proliferation. This potency was shown to be superior to CDK4/6 inhibitors and due to Cereblon-mediated target degradation.
- CDK4/6 bifunctional degraders were active in a CDK4/6 inhibitor resistant cell line and in multiple PDX CDK4/6 inhibitor resistant organoid models.
- CDK4/6 bifunctional degraders exhibited good tumor exposure when dosed orally, and induced a dose-dependent reduction in CDK4, CDK6, and pRB levels in MCF7 xenograft tumors. This resulted in dose dependent tumor growth inhibition and superior efficacy compared to CDK4/6 inhibitors.
- These degraders have also shown blood brain barrier penetration and superior inhibition of tumor growth in an MCF7 intracranial mouse model compared to a CDK4/6 inhibitor.
- The combination of the enhanced efficacy, activity in resistant cell lines and blood brain barrier penetration demonstrate the potential for CDK4/6 degraders in a range of potential cancer indications.
Title: Development of bifunctional CRBN-SOS1 degraders for treatment of mutant KRAS cancers
Presenter: Kyle Begovich, Ph.D., Senior Scientist - Biology
Abstract #: 1578
Session: New Therapeutic Targeted Agents
Session Date and Time: Monday, April 17, 2023, at 9:00 a.m. ET
- KRAS is the most frequently mutated cancer-causing oncogene and is mutated in over 20% of all human cancers, including an estimated 90% of pancreatic tumors and 45% of colorectal tumors. Combinational therapeutic approaches are needed to avoid drug resistance in the treatment of KRAS mutant cancers, such as coupling KRAS inhibition with a blockade of its guanine exchange factor (GEF), SOS1, to keep KRAS in its inactive state as well as prevent upstream pathway reactivation.
- Biotheryx SOS1 degraders demonstrated antiproliferative effects across a range of KRAS-mutated cell lines. Consistent with this notion, treatment with SOS1 degraders in KRAS-mutant xenograft models resulted in greater than 90% degradation of SOS1 in tumors and subsequently led to significant tumor growth inhibition as a single agent.
- SOS1 degraders also exhibited synergistic effects with other RAS/MAPK inhibitors in in vitro studies as well as KRAS-mutant xenograft models.
- These data support the potential of SOS1 degradation as a valuable treatment option for a range of KRAS mutant cancers.
Following the presentations at the meeting, PDF copies of the presentations and posters will be available in the "Publications and Presentations" section of Biotheryx's website.
About Biotheryx, Inc.
Biotheryx is a biopharmaceutical company discovering and developing a portfolio of first-in-class protein degraders, including bifunctional degraders and molecular glues. Our initial focus is on deploying the differentiated potential of degraders towards validated targets in cancer and inflammatory disease. Members of our founding and scientific teams previously developed the first U.S. Food and Drug Administration (FDA) approved modulators of Cereblon, the most widely validated E3 ligase involved in protein degradation, and we have applied our expertise in Cereblon binding to build our proprietary PRODEGY platform. Our pipeline of bifunctional degraders includes BTX-9341, the first-ever degrader of CDK4/6 for solid tumors, and the first-ever degraders of SOS1 for pan-KRAS mutant cancers and PDE4 for inflammatory diseases. Our pipeline of molecular glues includes BTX-1188, a rationally designed, dual-targeting molecular glue degrader of GSPT1 and IKZF1/3 for acute myeloid leukemia and solid tumors, and undisclosed oncology targets through our research collaboration and license agreement with Incyte. For more information, please visit www.biotheryx.com and engage with us on LinkedIn.