Insilico Medicine, a clinical-stage generative artificial intelligence (AI)-driven drug discovery company, announces that it has developed an orally bioavailable preclinical candidate compound targeting KIF18A for the treatment of advanced solid tumours with TP53 mutation, especially relevant for high-grade serous ovarian cancer (HGSOC), triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC).

Chromosomal instability (CIN) is a hallmark of cancer caused by persistent errors in chromosome segregation during mitosis.

KIF18A is a motor protein that moves along microtubules and plays a crucial role in the process of mitosis.

Research shows that inhibitors of the KIF18A activate the mitotic checkpoint and selectively kill chromosomally unstable cancer cells.

Therefore, targeting CIN cancers by inhibiting KIF18A represents a promising new therapeutic strategy.

ISM9682 is a highly selective and potentially best-in-class small molecule inhibitor of KIF18A.

Using Chemistry42, Insilico’s generative chemistry engine, Insilico’s R&D team designed a series of novel macrocyclic structures targeting KIF18A.

After synthesizing and evaluating approximately 110 compounds, ISM9682 was nominated as a preclinical candidate.

In preclinical studies, ISM9682 has demonstrated broad anti-tumor activity in HGSOC, TNBC and NSCLC CIN cell lines.

It has also shown potent in vivo efficacy in multiple CDX models.

Additionally, the molecule has a favourable oral bioavailability and a good safety margin.

Insilico will further explore the potential combination effects of ISM9682 with mitotic/DNA repair inhibitors, such as Olaparib, and expand into broader indications.

“Targeting KIF18A to inhibit CIN cancers is an emerging therapeutic strategy in drug discovery with broad clinical prospects,” said Feng Ren, PhD, co-CEO and Chief Scientific Officer of Insilico Medicine.

“It is exciting that our team discovered a distinct molecule with desirable safety and promising efficacy using Chemistry42. As the IND-enabling study progresses, we are looking forward to identifying the best indication and advancing the program to the clinical stage.”

Combining AI and human expertise, Insilico has advanced a robust pipeline of promising therapeutics for cancer and other diseases, nominating 17 PCCs since 2021 and advancing five to the clinical stage.

The Company has signed major global out-licensing deals on a number of its assets, including Exelixis and Menarini in 2023.

In addition, Insilico launched significant updates to its Pharma.AI platform in November 2023, introducing a groundbreaking Copilot feature that represents a leap forward in the synergy between large language models and proprietary AI frameworks.

Source: Insilico Medicine