Insilico MedicineInsilico Medicine has made a significant breakthrough with its AI-designed USP1 inhibitor, ISM3091. The US Food and Drug Administration (FDA) has accepted Insilico’s Investigational New Drug (IND) application for this promising drug, marking a significant milestone for AI-assisted drug discovery.

“The FDA’s acceptance of our IND for ISM3091 signifies that the FDA recognizes its potential value, and we can now open clinical trial sites across multiple centers and begin to study ISM3091 in human patients who may benefit from novel therapies,” said Dr. Sujata Rao, senior vice president, head of global clinical development at Insilico Medicine.

The company’s discovery and development of drug candidates, including ISM3091 and ISM001-055, which has also progressed to the clinic, showcases the efficiency and cost-effectiveness of AI in accelerating drug development. ISM001-055, a potentially first-in-class small molecule inhibitor for idiopathic pulmonary fibrosis (IPF).

Insilico discovered and modified both candidates with its proprietary generative AI platform, Chemistry42. The company boasts on its website that the automated machine learning platform for drug design can identify novel lead-like structures in a matter of days.

The therapeutic potential of AI-designed USP1 inhibitors in oncology

Ubiquitin-specific protease 1 (USP1) inhibitors like ISM3091 represent a promising class of oncology drugs. USP1 is an enzyme involved in DNA damage repair and other cellular processes. It is overexpressed in various cancer types, making it an attractive target for chemotherapy.

Diving deeper into the mechanism of action, USP1 is a deubiquitinase involved in DNA damage repair by modulating the ubiquitination of major regulators, such as PCNA and FANCD2. Its dysregulation, common in many cancers, can influence cancer therapy outcomes. Inhibitors of USP1 have the potential to bolster the effectiveness of anticancer drugs, promoting increased cancer cell death through downregulation of survivin and miR-216a-5p-mediated upregulation of DR5.

In addition to ISM3091, another USP1 inhibitor, KSQ-4279 from KSQ Therapeutics, is also in a phase 1 clinical study. Initial results indicate that KSQ-4279 may prevent the proliferation of cancer cell lines with BRCA mutations or other HRD alterations. When combined with PARP inhibitors, KSQ-4279 demonstrated synergistic effects, particularly in cell lines that were partially or wholly resistant to each agent on its own.

Unveiling ISM3091: Insilico’s AI-designed, USP1 inhibitor with promising preclinical performance

ISM3091 is a selective inhibitor of USP1. Preclinical studies have demonstrated its efficacy against various tumor cell lines. In such tests, ISM3091 demonstrated strong anti-proliferative activity, including against cells with BRCA1 mutations and other homologous recombination repair deficiencies. One of the distinguishing attributes of ISM3091 is its demonstrated potential in tackling a significant challenge in cancer therapy: resistance to PARP inhibitors.

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In addition, Good Laboratory Practice (GLP) toxicology studies, indicated minimal gastrointestinal or hematological toxicity and demonstrated overall favorable pharmacokinetic profiles and good tolerability.

This orally available and highly selective small molecule inhibitor ISM3091 has shown encouraging results in preclinical trials across multiple tumor cell lines and in vivo models, according to the American Association for Cancer Research (AACR) Journal.

In addition to scientific data, the IND application package included a comprehensive outline of the clinical trial design, from patient selection criteria to study endpoints, as well as methods for safety monitoring during drug administration. “Further, since this is to be a Phase 1 study, it serves as the initial introduction of ISM3091 into humans, and thus the FDA also needed to be satisfied that we are committed to ensuring that the quality and safety of our investigational drug (ISM3091) is maintained, and that we have the appropriate quality control (QC) procedures in effect,” Rao said.

Strategic advantages of IND approval and AI in drug development

Attaining IND approval promises to have strategic advantages for Insilico, offering potential for partnerships, funding and engagement with stakeholders. “With regards to AI-based drug development, Insilico has demonstrated with increasing sophistication of generative AI technologies, the ability to discover novel targets and develop new therapeutics at a rapid pace, reducing the time to candidate nomination significantly,” Rao said. “The impact on drug development is considerable since this further allows reduction in risk, expense, and the lengthy timelines that we see with more traditional approaches, and drives earlier clinical studies.”

Drawing from the preclinical data, Insilico Medicine posits that ISM3091 could become a valuable addition to the treatment options for BRCA-mutated/HRD advanced tumors. The launch of the multicenter phase 1 study for ISM3091 marks the first step in validating this assertion. The trial aims to assess safety, tolerability, pharmacokinetics, and preliminary efficacy in patients with advanced solid tumors. The primary objective of this Phase 1 study is to assess the safety and tolerability of ISM3091 in patients with advanced solid tumors, with antitumor activity (or effectiveness of the treatment) being a secondary objective,” Rao said.

Assessing the effectiveness of the AI-designed USP1 inhibitor, ISM3091, in the clinical trial

Eligibility will include patients with BRCA-mutated breast, BRCA-mutated ovarian and HRD (including BRCA-mutated) prostate cancer. Specific endpoints for the secondary objective include: ORR (Overall Response Rate), DoR (Duration of Response), PFS (Progression-Free Survival), and OS (Overall Survival) according to PCWG3 (Prostate Cancer Working Group) for prostate cancer and RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 for all other tumors; and PSA (Prostate-Specific Antigen) response and time-to-PSA progression for prostate cancers.

Future directions for ISM3091 and Insilico’s AI-powered drug development

The company’s successful discovery and development of drug candidates, such as ISM3091 and the previously progressed anti-fibrotic drug, ISM001-055, for idiopathic pulmonary fibrosis, showcases the efficiency and cost-effectiveness of their AI-powered platform in accelerating drug development.

In April, Insilico announced that it had designed and synthesized a potential hepatocellular carcinoma (HCC) drug in only 30 days. Now, the focus shifts back to their promising USP1 inhibitor, ISM3091. “Future research and development efforts with ISM3091 would include patient populations beyond BRCA-mutated tumors, and also evaluate effects of ISM3091 in combination with PARP inhibitors as well as other established/investigational agents,” Rao said.

With the advance of ISM3091 to the clinic and the latest regulatory milestone of Insilico’s AI-powered drug development platform, the company appears poised to continue pushing boundaries in drug discovery.