At the American Association for Cancer Research Annual Meeting 2024 (AACR 2024), which takes place in San Diego from April 5–10, five preclinical programs have been accepted as poster presentations, according to Insilico Medicine (“Insilico”), a clinical-stage generative artificial intelligence (AI) driven drug discovery company. The AACR website now has abstracts available.
Pharma.AI, Insilico’s validated and commercially viable AI drug discovery platform, powers the company’s drug discovery efforts. It operates in the fields of biology, chemistry, and clinical medicine and offers cutting-edge generative AI tools to the biotechnology and pharmaceutical industries, speeding up their own internal research and development.
Below is a synopsis of the five preclinical programs that Insilico will be presenting at AACR:
1. Abstract Title: ISM9342A: a new, powerful, orally accessible WRN inhibitor that inhibits the growth of MSI-H tumors has been discovered and characterized preclinically.
Category of Session: DNA Damage and Repair 1
Title of Session: Genetics and Molecular/Cellular Biology
Date and hour of the session: April 7, 2024, 1:30 PM to 5:00 PM
412 is the published abstract number.
WRN is known to be a viable target for research on synthetic lethality in MSI-H cancers and is essential for preserving genomic integrity and repairing damaged DNA.
Insilico presented the design, development, and testing of two strong, selective WRN helicase inhibitors, ISM9432A and ISM2196, in this preclinical study. Both compounds show promising drug-like and ADMET characteristics. In comparison to the well-known WRN helicase inhibitor, preclinical research on MSI-H xenografted cancer models demonstrated the strong anti-tumor activity of ISM2196. Given that ISM2196 has a lower effective dose than current WRN helicase inhibitors, it is a prime option for additional research.
2. Abstract Title: In preclinical models of malignancies with dysregulated hippocampal pathways, ISM6331, a new and powerful pan-TEAD inhibitor, shows significant anti-tumor action.
Topic of the session: Cell Signaling Elements as Medicinal Targets
Title of Session: Genetics and Molecular/Cellular Biology
Date and hour of the session: April 8, 2024, 9:00 AM–12:30 PM
1656 is the published abstract number.
TEAD proteins are known to be essential Hippo pathway transcription factors, and the transcriptional output of this route is crucial for the development of tumors, metastases, cancer metabolism, immunology, and drug resistance.
Using its generative AI platform, Insilico delivered ISM6331, a new and powerful TEAD inhibitor against TEAD1-4. ISM6331 demonstrated strong anti-tumor effects at low dosages in animal models and a wide anti-tumor effect across a variety of cell lines in preclinical investigations. In vitro and in vivo models, ISM6331 also demonstrated synergy with EGFR or KRAS inhibitors in suppressing the development of tumor cells and overcoming medication resistance. Furthermore, ISM6331 demonstrated exceptional pharmacokinetic characteristics in several preclinical species and shown good tolerance in GLP toxicity investigations. According to recent study, ISM6331 shows promise both as a monotherapy and in combination with targeted medicines for the treatment of cancers whose Hippo pathway is dysregulated.
3. Abstract Title: In preclinical research, ISM9182A, a new HPK1 inhibitor, has immune modulatory activity and strong monotherapy anti-tumor effects.
Topic of the session: Tumor Adaptive Immunity
Title of Session: Immunology
Date and hour of the session: April 9, 2024, 9:00 AM–12:30 PM
3967 is the published abstract number.
Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) is a desirable target in immuno-oncology for a variety of tumor types since it negatively influences immune cells such as T cells, B cells, and dendritic cells.
ISM9182A was shown to be a new, powerful, and specific inhibitor of HPK1, with effects on human PBMCs that were dose-dependent, high family selectivity, and nanomolar enzymatic potency. Furthermore, in vivo research shown that ISM9182A had strong anticancer effects in a CT-26 syngeneic mouse model, high oral bioavailability in many species, and favorable ADME characteristics.
4. Abstract Title: ISM8001, a covalent and specific FGFR2/FGFR3 dual inhibitor with potent anti-tumor efficacy as a monotherapy against advanced solid tumors, has been discovered and characterized preclinically.
Topic of the session: Progress in Immune Biology, Therapeutic Response, and Cancer Prognostication
Title of Session: Molecular/Cellular Biology and Immunology, Genetics
Date and hour of the session: April 9, 2024, 1:30 PM to 5:00 PM
Number of published abstract: 5582
Numerous solid cancers are primarily driven by oncogenic changes in fibroblast growth factor receptors 2 and 3 (FGFR2 and FGFR3).
Orally administered, ISM8001 is a highly selective dual inhibitor that spares FGFR1/4 while targeting FGFR2/3. The substance shown to be more potent in gatekeeper and molecular brake mutant-resistant animals, as well as in several FGFR2/3-driven efficacy models. In addition, it displayed acceptable safety margins, low effective doses, and positive DMPK profiles to support greater human doses.
5. Abstract Title: Against chromosomally unstable tumors, ISM9682A, a new and powerful KIF18A inhibitor, exhibits strong antitumor effects.
Category of session: Pharmacological Targeting of Proteins in the Cell Cycle
Title of Session: Genetics and Molecular/Cellular Biology
Date and hour of the session: April 9, 2024, 1:30 PM to 5:00 PM
5727 is the published abstract number.
Targeting KIF18A, a member of the kinesin-8 subfamily, may be effective against tumors with high levels of chromosomal instability, according to studies.
Insilico announces ISM9682A, a new KIF18A inhibitor with outstanding selectivity and efficacy, in this study. Preclinical investigations revealed that ISM9682A exhibited superior anti-proliferative activity as a monotherapy in various cancer cell lines. Additionally, both enzymatic and cellular assays indicated a prolonged drug-target residence time. Significantly, ISM9682A showed strong biological potency and high selectivity in addition to favorable in vitro ADMET properties, good oral bioavailability across several preclinical species, and outstanding in vivo exposure and clearance.
As a leader in the application of generative AI to drug discovery and development, Insilico Medicine has made significant advances in the treatment of a variety of illnesses, including aging-related disorders, cancer, fibrosis, and immunology. Within its extensive portfolio of more than 30 assets, Insilico has nominated 18 preclinical candidates since 2021 and has progressed six pathways to the clinical stage. The business most recently released a history in Nature Biotechnology of its lead AI-discovered and AI-designed medication for idiopathic pulmonary fibrosis, which is presently undergoing Phase II clinical trials.
