PI3Kα is a critical oncogenic driver in a broad range of solid tumors, including breast cancer, where activating mutations and pathway hyperactivation are frequently observed. Although two PI3Kα inhibitors have recently been approved by the FDA for breast cancer treatment, their clinical utility is significantly constrained by dose-limiting, on-target toxicities due to wild-type PI3Kα inhibition, most notably insulin resistance and hyperglycemia.
Antibody-drug conjugates (ADCs) offer a compelling strategy to enhance the therapeutic index of PI3Kα-targeted therapies. However, development of such agents has been hindered by the lack of sufficiently potent and selective PI3Kα inhibitors suitable as ADC payloads.
To address this, we utilized Accutar’s proprietary chimeric degrader platform to develop AC4847, a highly potent and selective PI3Kα degrader. By recruiting the Cereblon E3 ligase, AC4847 induced rapid, dose-dependent degradation of PI3Kα and suppression of downstream pAKT signaling across cell lines harboring diverse PI3Kα mutation statuses. AC4847 exhibited sub-nanomolar potency, approximately 100-fold more potent than the small-molecule PI3Kα inhibitor inavolisib, with minimal activity against other PI3K isoforms or Cereblon-associated neosubstrates. When conjugated to TROP2 or HER2 antibodies, AC4847-based degrader-antibody conjugates (DACs) elicited antigen-dependent PI3Kα degradation and robust anti-proliferative effects, with enhanced potency in cell lines expressing high levels of target antigen. In HER2-overexpressing BT-474 and JIMT-1 breast cancer xenograft models, a single dose of trastuzumab-conjugated PI3Kα DAC at 5 mg/kg or lower (administered once every three weeks) achieved durable tumor regression, accompanied by effective PI3Kα degradation and pAKT suppression. Notably, under equivalent plasma DAC exposures, no significant changes in blood glucose or insulin levels were observed in mice, rats, or non-human primates, contrasting with the pronounced metabolic toxicity seen with inavolisib at efficacious exposures.
In conclusion, these preclinical studies demonstrated that PI3Kα-targeted DACs using degrader AC4847 delivered potent, antigen-dependent anti-tumor efficacy while significantly reducing systemic toxicity compared to traditional small-molecule PI3Kα inhibitors. By leveraging the mechanistic advantages of chimeric degraders, such as catalytic target elimination, sustained pathway suppression dependent on protein resynthesis, and the ability to eliminate non-enzymatic scaffold functions, AC4847 offers a novel mode of action that enhances selectivity and durability of response. These attributes, combined with the targeted delivery enabled by antibody conjugation, support the advancement of AC4847-derived DACs into IND-enabling studies as a first-in-class therapeutic strategy for PI3Kα-driven cancers.
Develop AI solutions and optimize proprietary technology to accelerate drug discovery.
Design algorithms for protein structure analysis and biochemical processes using
advanced mathematical methods. Implement machine learning models and analyze
datasets using statistical inference. Document methodologies and production code.
Master’s degree in Mathematics or Computer Science required.
Two years of experience as an engineer or scientist, focusing on algorithm development
and machine learning.
Send resume to HR, Accutar Biotechnology Inc. 11100 NE 8th St, Suite #800, Bellevue,
WA 98004
CRANBURY, N.J.–(BUSINESS WIRE)–Accutar Biotechnology, Inc., a biotechnology company focusing on artificial intelligence (AI)-enabled drug discovery, announced today that the US Food and Drug Administration (FDA) has granted the investigation of AC699 a Fast Track designation for the treatment of patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative, estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression on or after at least 1 line of endocrine-based therapy. AC699 is an investigational orally bioavailable, chimeric degrader of estrogen receptor (ER) α currently in a Phase 1 trial.
ER-positive/HER2-negative subtype is the most common subtype of breast cancer (~70%), and mutations in the estrogen receptor 1 (ESR1) gene are common (20-40%) among ER-positive/HER2-negative patients who received endocrine therapy in the metastatic setting. AC699 has demonstrated objective response rate (ORR) of 50% in patients with an ESR1 mutation, in an ongoing Phase 1 trial, presented at ASCO 2024.
“Receiving Fast Track designation for AC699 from the FDA highlights their recognition of the serious and life-threatening nature of this malignancy, the critical unmet medical needs not fully addressed by existing therapies, and the potential of AC699 to fill in the gap,” said Jie Fan, Ph.D., Chief Executive Officer of Accutar Biotechnology, Inc. “We look forward to working closely with the FDA to optimize and expedite the development program.”
The FDA’s Fast Track process is designed to facilitate the development and expedite the review of novel drugs intended to treat serious conditions and address significant unmet medical needs. Companies that receive Fast Track designation are eligible for more frequent meetings and communications with the FDA during clinical development and potentially accelerated approval and priority review, if relevant criteria are met. For more information on Fast Track Designation, please visit the FDA’s website at https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fast-track.
About AC699 and the Phase 1 Study (AC699-001)
AC699 is an investigational orally bioavailable, chimeric degrader of estrogen receptor (ER) α. In preclinical studies, AC699 has demonstrated potent and selective protein degradation of ERα wildtype and mutants with favorable pharmacological properties, as well as promising anti-tumor activities in ER-positive animal tumor models.
The purpose of the Phase 1 multi-center, open-label study is to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of AC699 treatment in patients with ER-positive / HER2-negative locally advanced or metastatic breast cancer (NCT05654532). Additional information on this clinical trial can be found on www.clinicaltrials.gov.
About Accutar Biotechnology, Inc.
Accutar is a clinical stage biotech company focused on AI-enabled drug discovery, and its application to the discovery and development of clinically differentiated medicines.
Be transformative. For patients.
To learn more about Accutar, please visit us at www.accutarbio.com.
– Differentiated Mechanism of Action of a Chimeric Degrader as Compared to Fulvestrant and Novel SERDs –
– Treatment with AC699 Monotherapy Resulted in 21% ORR for All Evaluable Patients, and 50% for Those Who Had an ESR1 Mutation –
– Favorable Safety and Tolerability Profile at All Doses with No DLTs or ≥ Grade 3 Adverse Events Related to AC699 –
CRANBURY, N.J.–(BUSINESS WIRE)–Accutar Biotechnology, Inc., a biotechnology company focusing on artificial intelligence (AI)-enabled drug discovery, announced data from an ongoing Phase 1 study of AC699 monotherapy in patients with ER-positive / HER2-negative locally advanced or metastatic breast cancer. The data will be presented in a poster discussion session at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL on June 1, 2024.
AC699 is a potent and selective orally bioavailable, chimeric degrader of estrogen receptor (ER) α, and offers a potential new breast cancer treatment option based on a differentiated mechanism of action as compared to fulvestrant and novel SERDs with deeper ERα degradation as demonstrated in preclinical studies. AC699 is currently being evaluated in an ongoing Phase 1 clinical study as a single agent for the treatment of ER-positive / HER2-negative locally advanced or metastatic breast cancer (NCT05654532). The primary objectives are to evaluate the safety and tolerability of AC699. Secondary and exploratory objectives include pharmacokinetics, preliminary efficacy and pharmacodynamic evaluation. The study uses a 3+3 dose-escalation design, with once-daily oral dosing of AC699 at 100, 200, 300, 400, and 600 mg.
Phase 1 Study Results:
– As of April 8, 2024, 29 participants were enrolled and treated with AC699 at doses ranging from 100-400 mg. The participants had a median of 5 (range 2-10) prior lines of therapy, including 3 (range 1-8) prior lines in the metastatic setting
– The objective response rate was 21% (4/19) and increased to 50% (4/8) for those who had an ESR1 mutation
– There were no > Grade 3 drug-related adverse events (AEs), no dose limiting toxicities, no discontinuations and no dose reductions due to AEs
– AEs related to AC699 occurred in 38% of participants and included nausea (14%), hot flush (14%), and fatigue (10%)
– The maximum tolerated dose had not been reached yet
Details of the poster presentation at ASCO 2024 are as follows:
– Date/Time: June 1, 2024, 9:00 AM – 12:00 PM CDT
– Abstract Number: 3074
– Title: Preliminary results from a phase 1 study of AC699, an orally bioavailable chimeric estrogen receptor degrader, in patients with advanced or metastatic breast cancer.
– Session: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology
– Abstracts and full session details can be accessed through the ASCO meeting planner: Link
“We are extremely pleased with the groundbreaking safety and efficacy that AC699 has demonstrated thus far in Phase 1, with early evidence of its best-in-class potential, especially for patients with ESR1 mutations,” said Jie Fan, Ph.D., Chief Executive Officer of Accutar Biotechnology, Inc. “We look forward to completing the dose escalation portion of the study and starting the Phase 2 study soon. We believe that the oral dosing of AC699 and its differentiated mechanism of action, as compared to fulvestrant and novel SERDs, can potentially provide a new safe and effective treatment option for this patient population.”
About AC699 and the Phase 1 Study (AC699-001)
AC699 is an investigational orally bioavailable, chimeric degrader of estrogen receptor (ER) α. In preclinical studies, AC699 has demonstrated potent and selective protein degradation of ERα wildtype and mutants with favorable pharmacological properties, as well as promising anti-tumor activities in ER-positive animal tumor models.
The purpose of the Phase 1 multi-center, open-label study is to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of AC699 treatment in patients with ER-positive / HER2-negative locally advanced or metastatic breast cancer (NCT05654532). Additional information on this clinical trial can be found on www.clinicaltrials.gov.
About Accutar Biotechnology, Inc.
Accutar is a clinical stage biotech company focused on AI-enabled drug discovery, and its application to the discovery and development of clinically differentiated medicines.
Be transformative. For patients.
To learn more about Accutar, please visit us at www.accutarbio.com.
Coordinate and lead medical drug discovery clinical trial projects. Design and develop plans and process for specific drug during clinical trial process. Manage investigational product supplies and participate internal audits. Develop and review specific research-related documents. Develop and coordinate research project budget, management project progress and review project performance. Collect feedbacks and data from clinical trials and prepare reports for improvement of drug performance. Manage outsourced Central Lab activities. Serve as the contacts with partners and government agency in drug approving processing.
Requirements:
Master in Medicine or MD degree required. One years of experience in clinical trial project management related duties required.
Send resume to HR, Accutar Biotechnology Inc. 8 Clarke Dr. Ste. 4, Cranbury, NJ 08512
Requirements:
Master’s degree in Computer Science or Computer Engineering required. Two years of experience as Research Assistant, Researcher or Engineer or a similar position involving research in algorithms related duties required (accept either academic or industry experience).
Work Location: Bellevue, WA
Send resume to HR, Accutar Biotechnology, Inc., 11100 NE 8th St, Suite #800, Bellevue, WA 98004
Prostate cancer (PCa) is primarily driven by aberrant Androgen Receptor (AR) signaling. Although there has been substantial advancement in antiandrogen therapies, resistance to these treatments remains a significant obstacle, often marked by continuous or enhanced AR signaling in resistant tumors. While the dysregulation of the ubiquitination-based protein degradation process is instrumental in the accumulation of oncogenic proteins, including AR, the molecular mechanism of ubiquitination-driven AR degradation remains largely undefined. We identified UBE2J1 as the critical E2 ubiquitin-conjugating enzyme responsible for guiding AR ubiquitination and eventual degradation. The absence of UBE2J1, found in 5–15% of PCa patients, results in disrupted AR ubiquitination and degradation. This disruption leads to an accumulation of AR proteins, promoting resistance to antiandrogen treatments. By employing a ubiquitination-based AR degrader to adeptly restore AR ubiquitination, we reestablished AR degradation and inhibited the proliferation of antiandrogen-resistant PCa tumors. These findings underscore the fundamental role of UBE2J1 in AR degradation and illuminate an uncharted mechanism through which PCa maintains heightened AR protein levels, fostering resistance to antiandrogen therapies.
Evommune will leverage Accutar’s AI-empowered drug discovery platform for therapies targeting chronic inflammatory diseases
PALO ALTO, Calif. and CRANBURY, N.J., Nov. 28, 2023 /PRNewswire/ — Evommune, Inc., a biotechnology company discovering and developing new ways to treat immune-mediated inflammatory diseases, and Accutar Biotechnology Inc., a company focusing on artificial intelligence (AI)-empowered drug discovery, today announced a new strategic partnership focused on the discovery of novel small molecule drug candidates in chronic inflammatory diseases. The collaboration will leverage Accutar’s proprietary AI platform as well as Evommune’s expertise in the design and development of novel oral small molecule treatments against targets that are the root cause of chronic immune-mediated inflammatory diseases. Terms of the agreement will not be disclosed.
“We are excited to partner with Accutar, a leader in accelerating drug discovery, as we work to identify and validate novel targets that could have a profound impact on chronic inflammatory diseases,” said Jeegar Patel, Ph.D., Chief Scientific Officer of Evommune. “Accutar has a highly sophisticated hybrid approach of computational drug design and wet lab validation, and we plan to leverage this to overcome the limitations of traditional drug discovery methods on our targets of interest – allowing us to more efficiently design safe and efficacious therapies for complex chronic inflammatory diseases. Accutar is a team we know well, having collaborated with them on our current program targeting PKCθ, and we are thrilled to be expanding our partnership in a broader capacity.”
“Chronic inflammatory diseases represent the greatest threat to human health today, with nearly 60 percent of people in the U.S. alone suffering from at least one chronic condition,” said Jie Fan, Ph.D., Chief Executive Officer of Accutar. “We look forward to partnering with Evommune, a company with in-depth understanding in inflammatory diseases and extensive expertise in clinical development. By combining Evommune’s deep biological insights with our AI-empowered medicinal chemistry engine, and its application to the discovery and development of clinically differentiated medicine, we have great confidence we’ll be able to develop the next generation of therapies for chronic inflammatory diseases.”
About Evommune, Inc.
Evommune, Inc., a Palo Alto based biotech company, is creating game-changing science to treat immune-mediated inflammatory diseases by discovering, developing, and delivering therapies that address symptoms and halt progressive disease. For more information, please visit Evommune.com.
About Accutar Biotechnology, Inc.
Accutar is a clinical stage biotech company focused on AI-empowered drug discovery, and its application to the discovery and development of clinically differentiated medicines. To learn more about Accutar, please visit us at AccutarBio.com.
Contact:
Paul Laland
415.519.6610
Paul.laland@evommune.com
Jiaqi Ren
media@accutarbio.com
SOURCE Evommune, Inc.
Accutar Biotech Inc., a biotechnology company specializing in artificial intelligence (AI) – empowered drug discovery, today announced that Dr. Erika Hamilton, director of breast cancer research at Sarah Cannon Research Institute (SCRI), has joined the Scientific Advisory Board (“SAB”) of the company to advise on clinical trials of the company’s phase 1 breast cancer programs that are orally bioavailable, chimeric degrader molecules designed to target and degrade ERα protein with high potency and selectivity.
Dr. Hamilton is a leader in the field of both breast and gynecologic cancers. She had led numerous clinical trials, ranging from first-in-human phase I developmental trials to Phase III registrational trials. Her expertise led to her appointment as the chairperson of the ASCO Scientific Committee for Metastatic Breast Cancer, which is just one of her many recognitions and accomplishments. “We are honored to have Dr. Hamilton join our SAB at this critical inflection point for our company”, said Jie Fan, PhD, founder and CEO of Accutar. “Her innovative contributions to drug development, focus on advancing new therapies, and compassion for patients makes her the ideal person to help forge the next steps to bring our revolutionary medicine to patients.”
– Chimeric Degrader With a Differentiated Mechanism of Action vs. BTK Inhibitors by Removing Both Kinase And Scaffolding Functions of BTK –
– Broad BTK Mutant Coverage Designed to Overcome Resistance to Covalent And Non-Covalent BTK Inhibitors –
– Improved Selectivity Profile Sparing Common Off-Targets Observed for BTK Inhibitors –
CRANBURY, N.J.–(BUSINESS WIRE)–Accutar Biotechnology, Inc., a biotechnology company focusing on artificial intelligence (AI)-empowered drug discovery, today announced the dosing of the first patient in a Phase 1 study of AC0676, an orally bioavailable, chimeric degrader molecule designed to target and degrade Bruton’s Tyrosine Kinase (BTK) with high potency, selectivity, and broad mutant coverage.
“The initiation of this study distinguishes Accutar as the first company to successfully bring oral chimeric degraders against three different targets into the clinic,” said Jie Fan, Ph.D., Chief Executive Officer of Accutar Biotechnology, Inc. “Leveraging our protein crystallography and AI-empowered PPI-TAC (Protein-Protein Interaction Targeting Chimera) platforms, AC0676 was designed to potently and selectively degrade both wildtype BTK and BTK mutations that confer drug resistance to both covalent and non-covalent BTK inhibitors, including but not limited to C481S and kinase dead mutations such as L528W. We are excited about the differentiated therapeutic profile of AC0676 and its broad potential to treat patients with B-cell malignancies.”
The purpose of the Phase 1 multi-center, open-label study is to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of AC0676 treatment in patients with relapsed/refractory B-cell malignancies, including Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), non-GCB Diffuse Large B-cell Lymphoma (DLBCL), Mantle Cell Lymphoma (MCL), Follicular Lymphoma (FL), , Marginal Zone Lymphoma (MZL), or Waldenström Macroglobulinemia (WM). Additional information on this clinical trial can be found on www.clinicaltrials.gov (NCT05780034).
About AC0676
AC0676 is an investigational orally bioavailable, chimeric degrader of Bruton’s Tyrosine Kinase (BTK) for the potential treatment of relapsed/refractory B-cell malignancies. In preclinical studies, AC0676 has demonstrated potent and selective BTK protein degradation with broad coverage of BTK wildtype and mutants (including C481S, L528W, and others), favorable pharmacological properties, as well as promising anti-tumor activity in animal models.
About Accutar Biotechnology, Inc.
Accutar is a clinical stage biotech company focused on AI-empowered drug discovery, and its application to the discovery and development of clinically differentiated medicines.
Our Motto: Be transformative. For patients.
To learn more about Accutar, please visit us at www.accutarbio.com.