Alex Zhavoronkov, PhD, Insilico’s founder, chairman, and CEO

Insilico Medicine is entering the fast-growing scramble among drug developers to treat cancer by targeting KIF18A, identifying a preclinical candidate for the purpose with plans to eventually bring it into first in human trials.

ISM9682 is a highly selective oral small-molecule inhibitor of KIF18A—a mitotic kinesin motor protein shown to play a role in promoting the viability of chromosomal instability (CIN) cancer cells—with a novel macrocyclic structure that was designed from scratch using Insilico’s Chemistry42 generative AI platform, and thus differs from other KIF18A inhibitors under development.

ISM9682 is being developed against advanced solid tumors, in which mutations in CIN genes increase the probability that whole chromosomes or large fractions of chromosomes are gained or lost during cell division. The company has set no timeframe for the start of clinical trials for ISM9682, pending completion of IND-enabling study now under way.

“We look forward to advancing the program to the clinical stage as soon as possible,” Alex Zhavoronkov, PhD, Insilico’s founder, chairman, and CEO, told GEN Edge.

Zhavoronkov said Insilico concluded KIF18A was a promising target for advanced tumor treatment development through a correlation analysis for diseases and targets based on the company’s PandaOmics platform, which is designed to enable multi-omics discovery of novel targets.

KIF18A was found to rank high in various cancer types, including high-grade serous ovarian cancer (HGSOC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC).

“We further combined the analysis with extensive biological research and initiated an internal R&D program for KIF18A,” Zhavoronkov explained. “In this program, we used the structure-based molecular design approach of Chemistry 42 to design compounds targeting KIF18A, and the Hit compound with a novel macrocyclic structure stood out. We then proceeded to optimize the Hit compound.”

After synthesizing and testing approximately 110 KIF18A inhibitors, ISM9682 was selected as the company’s KIF18A inhibitor candidate. In preclinical studies, Zhavoronkov said, ISM9682 has shown broad anti-tumor activity in multiple cell lines and cell line-derived xenograft (CDX) models.  The molecule also showed a favorable oral bioavailability and good safety margin.

“Based on preclinical data, it is hypothesized that ISM9682 could show effect at a lower dose compared to KIF18A inhibitors with published data,” Zhavoronkov said.

Insilico plans to present data on its KIF18A inhibitor program at the American Association for Cancer Research (AACR) annual meeting, to be held April 5–10 in San Diego. The company also plans to show that data to companies interested in partnering with the company to develop ISM9682.

“With the support of Pharma.AI, the company’s proprietary AI drug discovery platform, Insilico’s program is progressing efficiently through preclinical development,” Zhavoronkov added. 

Competitive field 

ISM9682 joins a competitive field of cancer-fighting KIF18A inhibitors, of which the furthest into clinical development is sovilnesib (formerly AMG650), an Amgen-developed differentiated oral small molecule KIF18A inhibitor being developed to treat advanced solid tumors.  

Last year Volastra Therapeutics, a startup whose investors include Eli Lilly, licensed from Amgen exclusive rights worldwide to develop and commercialize its lead synthetic lethal target sovilnesib. In return, Volastra agreed to pay Amgen an undisclosed combination of cash and equity upfront, plus unspecified milestone payments and royalties.  

Volastra is expected during the first quarter to launch a Phase Ib trial (NCT06084416) designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of sovilnesib at different dose levels. The study is designed to establish the recommended Phase II dose (RP2D) of sovilnesib in subjects with high grade serous ovarian cancer (HGSOC). 

Sovilnesib is one of two oral small molecule KIF18A inhibitors being developed by Volastra.  

The other is VLS-1488, a wholly-owned candidate now under study in the Phase I portion of a Phase I/II trial (NCT05902988) assessing the drug’s safety, tolerability and preliminary efficacy in advanced solid tumors that are known to have high levels of chromosomal instability. The Phase I/II trial dosed its first patient in October, with a projected 120 patients to be enrolled, and a preliminary estimated completion date of December 2025. 

“Our KIF18A inhibitor traps chromosomally unstable tumor cells in mitosis—preventing them from proliferating, and ultimately leading to cell death—with minimal effects on normal, healthy cells. This selectivity is important since therapies that interfere with mitosis broadly—like many chemotherapies do today—can have toxic effects on normal dividing cells, making them difficult to tolerate by patients due to their adverse effects,” Christina Eng, PhD, Volastra VP and head of biology, explained on the company’s website. “KIF18A inhibitors represent “a unique class of mitotic regulators that will be efficacious against tumor cells but tolerated by normal cells.” 

Preclinical programs 

Among the various preclinical KIF18A inhibitor programs in development is the second lead program of Accent Therapeutics, which will be developed to treat TNBC and ovarian cancer: “We are currently investigating biomarker hypotheses to more fully define the patient population that will benefit most from this treatment,” the company states on its website. 

Last month, Accent completed a $75- million Series C financing, the proceeds of which will be used in part toward advancing the KIF18A inhibitor and its other lead program, a DHX9 inhibitor to treat breast, ovarian, colorectal and endometrial cancers, through early clinical development.

Accent plans to begin IND-enabling studies of its KIF18A inhibitor in the first half of this year, and says the financing will position it well to file INDs this year for the KIF18A and DHX9 programs. 

Also in preclinical phases is Program 2093, a research collaboration of Apeiron Therapeutics and the University of Vermont (UVM). Last week a team of researchers from Apeiron and UVM published a study in Frontiers in Molecular Biosciences showing KIF18A alpha-4 helix to be an effective target and demonstrating that small molecules targeting KIF18A selectively limit CIN tumor cell proliferation, resulting in phenotypically similar effects on mitosis at the single cell level compared to genetic perturbations.  

“Our results support the idea that KIF18A inhibition may serve as a promising therapeutic treatment for CIN tumor types including breast, colorectal, cervical, and ovarian cancer. Future work will focus on determining how the alpha-4 helix is altered by mutations in S284 or binding to inhibitory compounds,” the research team concluded.  

The study’s corresponding author, Jason Strumpff, PhD, of UVM, credited Katherine L. Schutt, PhD, a former postdoctoral associate now at Rezo Therapeutics, and Kira Fisher of UVM with spearheading the research. 

ISM9682 is Insilico’s 18th preclinical candidate nominated since 2021 from a pipeline that now includes more than 30 candidates. The company’s candidates are under study in six clinical trials—two of them in Phase II—with multiple programs in IND-enabling studies approaching IND filing.  

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