Insilico Medicine (“Insilico”), a clinical-stage generative artificial intelligence (AI)-driven drug discovery company, today announced that five preclinical programs have been accepted as poster presentations in the American Association for Cancer Research Annual Meeting 2024 (AACR 2024) happening April 5-10 in San Diego. Abstracts are now available on the AACR website.
Insilico’s drug discovery efforts are driven by its validated and commercially viable AI drug discovery platform, Pharma.AI, which works across biology, chemistry, and clinical medicine, providing the biotechnology and the pharmaceutical industry with advanced generative AI tools to accelerate their internal research and development.
A summary of Insilico's five preclinical programs to be presented at AACR is provided below:
1. Abstract Title：Discovery and preclinical characterization of ISM9342A, a novel, potent, and orally bioavailable WRN inhibitor that suppresses MSI-H tumor growth
Session category: DNA Damage and Repair 1
Session title：Molecular/Cellular Biology and Genetics
Session date & time: April 7, 2024, 1:30 PM - 5:00 PM
Published abstract number: 412
WRN is recognized as a promising target for synthetic lethality studies in MSI-H tumors and plays a crucial role in DNA repair and maintaining genomic integrity.
In this preclinical research, Insilico introduced the design, development, and evaluation of two selective, potent WRN helicase inhibitors, ISM9432A and ISM2196. Both compounds exhibit favorable ADMET and drug-like properties. The preclinical studies showed robust anti-tumor efficacy of ISM2196 in MSI-H xenografted cancer models relative to the known WRN helicase inhibitor. The lower efficacious dose of ISM2196 relative to existing WRN helicase inhibitors makes it an ideal candidate for further investigation.
2. Abstract Title：ISM6331, a novel and potent pan-TEAD inhibitor, exhibits strong anti-tumor activity in preclinical models of Hippo pathway-dysregulated cancers
Session category: Cell Signaling Components as Therapeutic Targets
Session title：Molecular/Cellular Biology and Genetics
Session date & time: April 8, 2024, 9:00 AM - 12:30 PM
Published abstract number: 1656
TEAD proteins are recognized as key transcription factors of the Hippo pathway and its transcriptional output plays an important role in tumor progression, metastasis, cancer metabolism, immunity, and drug resistance.
Insilico delivered ISM6331, a novel and potent TEAD inhibitor against TEAD1-4 by leveraging its generative AI platform. In preclinical studies, ISM6331 showed broad anti-tumor effect in multiple cell lines and potent efficacy at low doses in animal models. ISM6331 also showed synergism with EGFR or KRAS inhibitors in inhibiting tumor cell growth and overcame drug resistance in in vitro and in vivo models. In addition, ISM6331 showed excellent pharmacokinetic properties in multiple preclinical species and was well tolerated in GLP toxicity studies. The current research indicates ISM6331 has promising potential to treat Hippo pathway-dysregulated tumors as a monotherapy as well as in combination with targeted therapies.
3. Abstract Title：ISM9182A, a novel HPK1 inhibitor, exhibits immune modulatory activity and robust monotherapy anti-tumor effects in preclinical studies
Session category: Adaptive Immunity in Tumors
Session title：Immunology
Session date & time: April 9, 2024, 9:00 AM - 12:30 PM
Published abstract number: 3967
The hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) negatively regulates immune cells including T cells, B cells and dendritic cells, and is thus considered as an attractive immuno-oncology target in many tumor types.
In this research, ISM9182A was reported as a novel, potent, and selective inhibitor of HPK1, with nanomolar enzymatic potency, good family selectivity and dose-dependent pSLP76 inhibition effects in human PBMC. Moreover, In vivo studies revealed ISM9182A exhibited favorable ADME properties and good oral bioavailability across different species, as well as potent antitumor effects in a CT-26 syngeneic mouse model.
Session category: Advances in Cancer Prognostication, Therapeutic Response, and Immune Biology
Session title：Molecular/Cellular Biology and Genetics, immunology
Session date & time: April 9, 2024, 1:30 PM - 5:00 PM
Published abstract number: 5582
Oncogenic alterations in fibroblast growth factor receptors 2 and 3 (FGFR2 and FGFR3) are key drivers in multiple solid tumors.
ISM8001 is an orally available, highly selective dual inhibitor targeting FGFR2/3, and sparing FGFR1/4. The compound demonstrated superior potency in multiple FGFR2/3-driven efficacy models, and also in gatekeeper and molecular brake mutant-resistant models. It also showed favorable DMPK profiles, low efficacious dose, and desirable safety margin to support higher human dose.
5. Abstract Title：ISM9682A, a novel and potent KIF18A inhibitor, shows robust antitumor effects against chromosomally unstable cancers
Session category: Pharmacologic Targeting of Cell Cycle Proteins
Session title：Molecular/Cellular Biology and Genetics
Session date & time: April 9, 2024, 1:30 PM - 5:00 PM
Published abstract number: 5727
Studies have shown the potential of targeting KIF18A, a member of the kinesin-8 subfamily, against cancers exhibiting high chromosomal instability.
In this research, Insilico reports ISM9682A, a novel KIF18A inhibitor with high potency and selectivity. In preclinical studies, ISM9682A demonstrated excellent monotherapy anti-proliferative activity in multiple cancer cell lines, as well as a prolonged drug-target residence time indicated by both enzymatic and cellular assays. Notably, ISM9682A demonstrated not only robust biological potency and high selectivity, but also desirable in vitro ADMET characteristics, excellent in vivo exposure, clearance, and good oral bioavailability across multiple preclinical species.
Insilico Medicine is a pioneer in utilizing generative AI for drug discovery and development, and has delivered breakthroughs for healthcare in multiple disease areas, including fibrosis, cancer, immunology and aging-related diseases. Since 2021, Insilico has nominated 18 preclinical candidates in its comprehensive portfolio of over 30 assets and has advanced six pipelines to the clinical stage. Most recently, the company published a history of its lead AI-discovered and AI-designed drug for idiopathic pulmonary fibrosis, currently in Phase II clinical trials, in Nature Biotechnology.
About Insilico Medicine
Insilico Medicine, a global clinical-stage biotechnology company powered by generative AI, connects biology, chemistry, and clinical trial analysis using next-generation AI systems. The company has developed AI platforms that utilize deep generative models, reinforcement learning, transformers, and other modern machine learning techniques for novel target discovery and generating novel molecular structures with desired properties. Insilico Medicine is developing breakthrough solutions to discover and develop innovative drugs for cancer, fibrosis, immunity, central nervous system diseases, infectious diseases, autoimmune diseases, and aging-related diseases. www.insilico.com