KIF18A

KIF18A Inhibitor: Treating chromosomally unstable cancers with TP53 mutations (Out-licensed)

Assays Completed

Out-licensed

• In vivo efficacy studies

• In vivo PK-PD

• In vivo PK studies

• In vitro ADMET studies

• In vitro cell-based studies

• Toxicology studies

• Enzymatic studies

Target Rationale

Chromosome instability (CIN) is a hallmark of tumor cells caused by changes in the dynamics and control of microtubules that compromise the mitotic spindle. In sensitive CIN+ cells, KIF18A depletion results in profound chromosome alignment defects, multipolar spindles, and chromosome fragmentation, leading to extended spindle checkpoint activation and increased cell death.

Insilico Medicine KIF18A Inhibitor Summary – Out-licensed

• Novel structure generated by AI
• Effective therapy for treating solid tumors
• Potent in vitro and in vivo anti-cancer activities in CIN cancer models
• Promising drug-ability as an oral agent
• Excellent in vitro ADMET profiles & favorable oral exposure across preclinical species
• Significantly higher safety margin
• Overall good tolerability up to high doses in rodent and non-rodent models

Indication

CIN cancers: high-grade serous ovarian cancer (HGSOC), non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), colorectal cancer (CRC), etc.

• These types of cancers often exhibit a high frequency of chromosome instability (CIN) and TP53 mutations, making cancer cells susceptible to mitotic defects. The loss of KIF18A function results in persistent spindle assembly checkpoint (SAC) activation and prolonged mitosis due to the dysregulation of microtubule dynamics in CIN cancer cells, while having minimal impact on the normal division of euploid cells. Inhibitors targeting KIF18A aim to hinder the proliferation and survival of tumor cells. As a result, these cancers may derive therapeutic benefits from KIF18A inhibitors.

• ISM9682 is a potent KIF18A inhibitor with a novel scaffold developed from Chemistry42. It demonstrates potent anti-proliferation activity in multiple CIN-cancer cell lines and excellent efficacy in CDX models, which has the potential to serve as a therapeutic approach for CIN cancers.

Project Highlight

ISM developed an AI-designed KIF18A inhibitor with a novel macrocyclic scaffold. This inhibitor exhibited potent anti-proliferation activities in cancer cell lines and CDX models with CIN features, along with excellent ADMET profiles. It demonstrated favorable in vivo PK across preclinical species and exceptional safety margin in animal toxicology studies.