BTX-9341 demonstrated potent degradation of CDK4/6 and tumor growth regression in resistant cells in preclinical breast cancer models, along with robust blood brain barrier penetration
SOS1 degraders exhibited antiproliferative effects and inhibited tumor cell growth in a broad range of KRAS-mutated cell lines
SAN DIEGO, CA., May 25, 2023 — 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 two poster presentations at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, being held June 2–6, 2023, in Chicago, Illinois and online. The presentations highlight preclinical data for bifunctional degraders of CDK4/6, including development candidate BTX-9341, for the treatment of estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-), and of son of sevenless homolog 1 (SOS1) for the treatment of KRAS mutant cancers.
“These new preclinical data demonstrate the potential of our bifunctional CDK4/6 and SOS1 degraders to potently degrade their targets, ultimately effectively inhibiting tumor growth together with the strength of Biotheryx’s PRODEGY platform to efficiently design first-in-class degraders,” said Philippe Drouet, President and Chief Executive Officer of Biotheryx. “Besides these encouraging efficacy results, BTX-9341, our oral CDK4/6 development candidate, exhibited superior blood brain barrier penetration versus inhibitors and good tumor exposure when dosed orally. We look forward to advancing BTX-9341 towards clinical development to overcome drug resistance challenges faced by patients with solid tumors such as ER+/HER2- breast cancer.”
2023 ASCO Annual Meeting 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 #: 1083
Session: Breast Cancer – Metastatic
Session Date and Time: Sunday, June 4, 2023, at 8:00 a.m. CDT
- CDK4/6 inhibitors are used to treat ER+/ HER2- breast cancer, but some patients have exhibited innate resistance, and many are shown to develop acquired resistance after three years on therapy.
- BTX-9341, discovered and developed by Biotheryx’s proprietary PRODEGY platform, is a potent, Cereblon- and proteasome-dependent degrader of CDK4 and CDK6 in multiple breast cancer cell lines.
- BTX-9341 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, due to Cereblon-mediated target degradation.
- The CDK4/6 bifunctional degraders were active in a CDK4/6 inhibitor resistant cell line and in multiple PDX CDK4/6 inhibitor resistant organoid models.
- BTX-9341 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, tumor regression and superior efficacy compared to CDK4/6 inhibitors.
- BTX-9341 and its analogue bifunctional 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 CDK4/6 inhibitor resistant models 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 #: 3151
Session: Developmental Therapeutics – Molecularly Targeted Agents and Tumor Biology
Session Date and Time: Saturday, June 3, 2023, at 8:00 a.m. CDT
- 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 cancer, 45% of colorectal cancer and 30% of lung cancer. Combination therapeutic approaches are likely 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’s SOS1 bifunctional degraders demonstrated antiproliferative effects across a range of KRAS-mutant cell lines. 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 pathway inhibitors, such as KRAS G12C, KRASG12D, EGFR and MEK inhibitors in in vitro studies as well as in KRAS-mutant xenograft models.
- These data support the potential of SOS1 degradation as a valuable treatment option for a range of KRAS mutant cancers, as a monotherapy and in combination with other RAS-MAPK pathway inhibitors.
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.