ULK1

Osaka, Japan and Waltham, Massachusetts, June 11, 2024 – Ono Pharmaceutical, Co., Ltd. (Chairman and CEO: Gyo Sagara, “Ono”) today announced that it has successfully completed the tender offer, previously announced on April 30, 2024 to acquire all outstanding shares of common stock of a US biopharmaceutical company, Deciphera Pharmaceuticals, Inc. (Nasdaq: DCPH, CEO: Steven L. Hoerter, “Deciphera”) for US$25.60 per share (total amount of approximately US$2.4 billion) net to the seller in cash, without interest thereon and less any applicable withholding taxes, through its wholly owned subsidiary, Topaz Merger Sub, Inc. (“Merger Sub”), established in the State of Delaware, United States, solely for the purpose of engaging in the transactions contemplated in the Merger Agreement.
　The tender offer commenced on May 13, 2024, New York City time, and, as set forth below, expired at one minute after 11:59 p.m., New York City time, on June 10, 2024.

　On June 11, 2024, following the completion of the tender offer, Merger Sub merged with and into Deciphera with Deciphera continuing as the surviving corporation and a wholly owned subsidiary of Ono. In connection with the acquisition, Deciphera shares ceased to be traded on Nasdaq as of the date of closing of the acquisition and shares of Deciphera’s common stock will be delisted from Nasdaq.

　“We are very pleased to welcome Deciphera into the family,” said Gyo Sagara, Chairman and CEO of Ono. “Through this acquisition, we will leverage Deciphera's excellent research and development capabilities in the oncology field and its sales power in Europe and the United States, and work to further accelerate the expansion of our pipeline and global expansion, which are part of our growth strategies.”

　"We are excited to enter a new phase as part of the family of Ono Pharmaceuticals, that has as its mission to contribute to society through the discovery and development of innovative drugs, under the corporate philosophy “Dedicated to the Fight against Disease and Pain,”” said Steven L. Hoerter, President and CEO of Deciphera. “By fully leveraging the research and development capabilities and commercialization platforms of both companies, we look forward to significantly contributing to the growth of the Ono Group as a global specialty pharma company.”

Ono Pharmaceutical agreed to acquire Deciphera Pharmaceuticals for $25.60 per share in cash, representing a total equity value of $2.4 billion, bolstering the Japanese firm’s oncology portfolio. Deciphera’s sole marketed product is the KIT inhibitor Qinlock (ripretinib), whilst its pipeline includes the CSF1R inhibitor vimseltinib and the ULK inhibitor DCC-3116.Gyo Sagara, chief executive of Ono, said “we expect that this acquisition…will not only expand Ono's target oncology portfolio, but also accelerate Ono's business development in the [US] and Europe, and strengthen kinase drug discovery research.”Qinlock is approved in the US, EU and more than 40 markets as a fourth-line  treatment for gastrointestinal stromal tumours (GIST). However, efforts to expand its use in earlier settings fell flat in 2021 when the drug failed to significantly prolong progression-free survival (PFS) in the Phase III INTRIGUE study against Pfizer's Sutent (sunitinib) in patients with second-line GIST.Deciphera is currently investigating Qinlock in the late-stage INSIGHT trial for second-line GIST patients with mutations in KIT exon 11 and 17 and/or 18 and the absence of mutations in KIT exon 9, 13, and/or 14. Meanwhile, vimseltinib is expected to be filed with regulators later this year after meeting the primary endpoint of the Phase III MOTION study in patients with tenosynovial giant cell tumours not amenable to surgery.The boards of both companies have unanimously approved the transaction, which is expected to close in the third quarter. The price of the deal represents a premium of 74.7% over Deciphera’s closing share price on April 26.

AMP-activated Protein Kinase (AMPK) is a heterotrimeric protein consisting of alpha (α) subunit (63kD), beta (β) (30kD), and gamma (γ) (37-63kD) subunits. The alpha subunit has a catalytic role, while the beta and gamma subunits serve important roles in maintaining the stability of the trimer and the specificity of the substrates. When AMP binds to the gamma subunit, it induces a conformational change that activates the complex, making it more susceptible to phosphorylation activation by upstream kinases of AMPK. AMPK maintains cellular energy balance by affecting multiple stages of cellular metabolism. When intracellular ATP levels decrease, AMPK inhibits glycogen, fat, and cholesterol synthesis to reduce ATP usage, and promotes fatty acid oxidation and glucose transport to increase ATP production. Hence, AMPK is considered a switch regulating cellular energy metabolism. As a low ATP sensor, AMPK maintains ATP homeostasis and adjusts downstream signaling pathways to maintain optimal mitochondrial status. Mitochondrial damage or lack of AMPK activation, including respiratory chain complex inhibitors such as the diabetes drug metformin, rotenone a Parkinson's-disease causing herbicide, proton clusters, ATP synthase inhibitors and mitochondrial DNA depletion or mutations, AMPK becomes the protector of mitochondria. In yeast 206, Caenorhabditis elegans 207-209, and Drosophila 210, AMPK is linked with mitochondria, representing an evolutionarily conserved function of AMPK. In eukaryotes, AMPK is activated when mitochondrial function or ATP production is impaired. Interestingly, there is no excess of AMPK substrates to maintain mitochondrial health, as mitochondrial integrity is the central medium of cellular energetics. The preference for specific AMPK complexes to locate at or near mitochondria and respond to mitochondrial-specific stressors is yet to be investigated. In lysosomes, how the mitochondrial pool of AMPK interacts or relates to LKB156 is an interesting area for future research. Further study is required to understand how the interactions among mitochondria, AMPK, ULK1 and other kinases activated by energy stressors like PINK1 and TBK1, and differential protein phosphorylation, influence mitochondrial autophagy and cell division and/or fusion and apoptosis177,211-213. Interestingly, recent research has found that the pluripotency of immune cells and stem cells involve mitochondrial dynamics and health214-218. Finally, expanding the substrate pool of mitochondrial AMPK will aid in researching novel mechanisms through which AMPK regulates mitochondrial function. Given that metformin is an effective AMPK activator, these issues not only bear importance for understanding basic biology but also provide implications for over 150 million individuals worldwide who take metformin. Furthermore, research on the direct activators of AMPK for the treatment of cancer and metabolic diseases (Box 1) has underscored the importance of AMPK in biology, particularly mitochondrial biology, in relation to metabolism. The regulation of mitochondrial health by metformin and other AMPK activators is one mechanism through which type 2 diabetes can be ameliorated, and is also one of the reasons why exercise and caloric restriction can improve health and extend the lifespan.  How do they work?From a biomedical perspective, AMPK inhibitors refer to a class of drugs or compounds that inhibit the activity of adenosine monophosphate-activated protein kinase (AMPK). AMPK is an enzyme that plays a crucial role in regulating cellular energy homeostasis. It is activated when cellular energy levels are low, and it helps restore energy balance by promoting processes such as glucose uptake and fatty acid oxidation, while inhibiting energy-consuming pathways like protein synthesis. AMPK inhibitors, on the other hand, work by blocking the activation or function of AMPK. By doing so, they can modulate various cellular processes and signaling pathways. These inhibitors have been studied for their potential therapeutic applications in various diseases, including cancer, metabolic disorders, and neurodegenerative diseases. In cancer research, AMPK inhibitors have been investigated as potential anti-cancer agents. By inhibiting AMPK, these drugs aim to disrupt cancer cell metabolism, which is often dysregulated and dependent on altered energy pathways. Additionally, AMPK inhibitors may also enhance the efficacy of other anti-cancer treatments, such as chemotherapy or radiation therapy. In the context of metabolic disorders like type 2 diabetes and obesity, AMPK inhibitors have been explored as a potential strategy to modulate glucose and lipid metabolism. By inhibiting AMPK, these compounds may alter the balance between energy storage and utilization, potentially leading to improved glucose control and weight management. It's important to note that the development and use of AMPK inhibitors require careful consideration of their potential side effects and impact on normal cellular functions. While these inhibitors hold promise as therapeutic agents, further research is needed to fully understand their mechanisms of action and evaluate their safety and efficacy in clinical settings. List of AMPK InhibitorsThe currently marketed AMPK inhibitors include: Sitagliptin/Metformin HydrochlorideEnavogliflozin/METFORMIN HYDROCHLORIDEMetformin Hydrochloride/Sitagliptin HydrochlorideEmpagliflozin/Linagliptin/Metformin HydrochlorideMetformin/Remogliflozin etabonateAnagliptin/Metformin HydrochlorideAtorvastatin Calcium Hydrate/Metformin HydrochlorideErtugliflozin/Metformin HydrochlorideEvogliptin Tartrate/Metformin HydrochlorideEmpagliflozin/metformin HydrochlorideFor more information, please click on the image below. What are AMPK inhibitors used for?AMPK inhibitors has long been in the spotlight as a potential target for the treatment of diseases associated with metabolic disorders, including diabetes, obesity and fatty liver, as well as cancer. For more information, please click on the image below to log in and search. How to obtain the latest development progress of AMPK inhibitors?In the Synapse database, you can keep abreast of the latest research and development advances of AMPK inhibitors anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!