Chinese biotech startup Lynk Pharmaceuticals Co. Ltd., of Hangzhou, has in-licensed global rights from Kobe University and Riken Research Institute in Japan to develop renin-angiotensin system (RAS) inhibitors, which have a novel mechanism of action that can increase chances of developing anti-RAS cancer drugs.

The compound candidates were derived from Kobe University and Riken’s early structural biology and screening research back in 2013. Seven years later, Lynk is contributing efforts in medicinal chemistry and drug design to develop them into anticancer drugs, while Kobe University will continue to provide the Chinese startup with screening and structural support.

The goal of this pact is to develop RAS inhibitors that can target a broader range of undruggable RAS onco-drivers and to ultimately develop the compounds for clinical use. Financial terms were not disclosed.

Lynk’s CEO Zhaokui Wan called RAS “a decades-old undruggable target,” and said the company is taking a “very ambitious approach” to challenge it.

“We’ve got the global rights and we aim to advance the RAS inhibitors to the clinic then the global market, not just in China,” Wan told BioWorld. “Some [multinational corporations] have expressed interest in working with us on this project.”

RAS alterations are associated with 20% to 30% of all human cancers, especially pancreatic, colon and lung adenocarcinomas. Lynk said although there has been progress toward irreversible binding the KRAS G12C subset, other more dominant KRAS mutants such as G12V and G12D remain an issue.

The biotech industry has been working on RAS inhibitors to treat cancer since the target was first identified in the 1960s. Amgen Inc.’s AMG-510 (sotorasib), the first KRAS G12C inhibitor to reach the clinic, has now obtained orphan drug status from the FDA for both KRAS G12C-positive non-small-cell lung cancer (NSCLC) and colorectal cancer. The Thousand Oaks, Calif.-based company reported positive phase I data of AMG-510 last year and has initiated a randomized global phase III confirmatory study in NSCLC.

Chinese biotech giant Beigene Ltd. is also helping to advance AMG-510. Beigene and Amgen entered a $2.7 billion deal last year to share global R&D costs for AMG-510 and 19 other drug candidates.

Meanwhile, Kobe University’s anti-RAS drug discovery can be dated back to 2013, when a research group led by Tohru Kataoka and Fumi Shima of Kobe University Graduate School of Medicine discovered low molecular weight compounds that exhibited antitumor activity by inhibiting the functions of the RAS oncogene products. The Japanese university said these compounds “serve as a scaffold for the development of molecularly targeted anticancer drugs for RAS.”

Kobe University’s researchers worked with Japan Synchrotron Radiation Research Institute and Riken to determine novel crystal structures of RAS and recognized druggable pocket structures on their surface. They also applied structure-based drug design and found three compounds that fit into one of the pockets.

According to the researchers, these compounds showed potent activity in blocking the binding of RAS to their multiple target proteins such as RAF kinases and PI3Ks. They also demonstrated antitumor activity on a xenograft of human colon carcinoma cells carrying the active RAS mutation.

The Japanese researcher also noted that the compounds they discovered are different in terms of the mechanism of action, showing stronger biochemical and cellular activities vs. RAS inhibitors being developed by Genentech Inc. and Abbott Laboratories Inc., they said. However, the researchers also said their compounds’ inhibitory activity was not particularly potent in the clinic.

With hopes to advancing its discovery to the clinic with Lynk, researchers from Kobe University will continue to provide screening and structural support.

Previously, they used computer-docking simulations to screen candidate compounds that bind to the surface pocket of RAS; used cancer cells carrying active RAS mutations to examine the compounds’ inhibitory activity in vitro and in cellular system; and tried a xenograft model in the nude mice transplanted with human colon cancer cells bearing KRAS G12V to examine in vivo antitumor activity of the compounds.

Established in 2018, Lynk has built a pipeline of nine drug candidates for oncology, immunology, and inflammatory diseases. Targets remain undisclosed but the drug candidates are said to have first-in-class or best-in-class potential.

In April, Lynk out-licensed a technology to an undisclosed U.S. firm, with an up-front payment of nearly $200 million and double-digit royalties on the sales. It also closed a series A financing round in the same month to pocket an undisclosed amount.

Wan remained tight-lipped about the company’s pipeline and financial status.

The startup was founded by industry insiders who previously served at big pharma such as Pfizer Inc., Johnson & Johnson, and Merck & Co. Inc. It is backed by five Chinese venture capital firms, including Decheng Capital, Kaitai Capital and Zheshang Innovest.

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