CCT-245737

Chk1, also known as checkpoint kinase 1, is a crucial protein kinase involved in the regulation of cell cycle progression and DNA damage response in the human body.  Chk1 is a serine/threonine (Ser/Thr) kinase encoded by the tumor suppressor gene Chk1, broadly existing in mammalian cells. In recent years, numerous domestic and international studies have indicated that Chk1 and its inhibitors can regulate the formation and development of tumors. Chk1 controls cell proliferation, being the key gene leading to an S/G1 and G2/M phase arrest after DNA damage, thus ensuring DNA repair and having vital surveillance function. Overexpression of Chk1 is observed in a variety of tumor tissues; it can participate in the onset and progression of certain tumors through specific molecular signaling pathways, and its aberrant expression levels are closely related to the therapeutic effects and prognosis of patients with hematological tumors. High expression of Chk1 is of great significance in the infiltration and metastasis of hematological tumor cells, and the appearance of Chk1 inhibitors provides a new direction for the treatment of malignant blood tumors. It plays a vital role in ensuring the integrity of the genome by monitoring DNA replication and repair processes. Chk1 acts as a checkpoint mediator, halting cell cycle progression in response to DNA damage or replication stress, allowing time for repair mechanisms to be activated. Dysregulation of Chk1 has been implicated in various diseases, including cancer, making it an attractive target for pharmaceutical interventions aimed at enhancing the efficacy of DNA-damaging therapies or developing novel anticancer treatments. So far, over 10 types of CHK1 inhibitors have entered clinical research, but no CHK1 inhibitor has been approved for marketing. Most CHK1 inhibitors have ceased development due to issues of efficacy and safety, and most of these compounds are administered through injections. Of the 4 types of CHK1 inhibitors that are currently still under clinical research, besides LY2606368, GDC0575, LY2880070, and CCT245737 can all be administered orally, greatly improving patient compliance. Therefore, the development of highly active, highly selective, and orally administrable new CHK1 inhibitors is an important direction for research in this field. Studies have found that the absence of FAM122A can promote tumor cell resistance to CHK1 and ATR inhibitors. Further research showed that CHK1 can phosphorylate the S37 site of FAM122A, which makes it move out of the nucleus and bind with 14-3-3, inhibiting its binding with the PP2A-B55α phosphatase complex, thereby improving the stability of WEE1 protein. Similarly, the absence of FAM122A will also increase the stability of WEE1 protein, activate the G2/M checkpoint, and prevent cells with DNA damage from entering mitosis, achieving resistance. Chk1 Competitive LandscapeAccording to Patsnap Synapse, as of 27 Sep 2023, there are a total of 30 Chk1 drugs worldwide, from 40 organizations, covering 42 indications, and conducting 79 clinical trials. 👇Please click on the picture link below for free registration or login directly if you have freemium accounts, you can browse the latest research progress on drugs , indications, organizations, clinical trials, clinical results, and drug patents related to this target.  Based on the analysis of the provided data, the current competitive landscape of target Chk1 shows that Eli Lilly & Co., Pfizer Inc., GSK Plc, and Baylor University are the companies with the highest development stages. Ovarian Cancer and Uterine Cervical Cancer are the indications with the most drugs in phase 2 development. Small molecule drugs are progressing rapidly under the current target, with a significant number of drugs in both phase 2 and preclinical stages. The United States, United Kingdom, and European Union are the countries/locations with the highest development stages, while China also shows progress in phase 1 development. Overall, the target Chk1 presents opportunities for further research and development in various indications and drug types, with a focus on small molecule drugs.

For targeted cancer therapy to work, it’s not enough to identify the right targets to hit with a drug. Just as important is selecting the patients appropriate for a given therapy. Scientists at Acrivon Therapeutics say their approach brings advantages over genetic-based patient selection. The Acrivon technology is approaching its first tests in humans with a drug acquired from a big pharmaceutical company. The IPO market, like the weather, has turned cold but Acrivon still found a way to raise nearly $100 million for its clinical trial plans. Acrivon came close to the nine-figure IPO it wanted, but it had to slash the stock price and sell more shares in order to pull it off. This past week, the biotech offered more than 7.5 million shares for $12.50 apiece, which raised $94.4 million. When Acrivon set preliminary terms for the IPO earlier this month, it planned to offer 5.9 million shares priced in the range of $16 to $18 each. Watertown, Massachusetts-based Acrivon was able to get closer to the $100 million mark by striking a separate and concurrent deal. Chione Limited, the largest shareholder in the company prior to the IPO, purchased 400,000 shares at the IPO price, raising another $5 million. Acrivon shares now trade on the Nasdaq under the stock symbol “ACRV.” Matching a cancer drug to a patient is typically done according to genomics. That works when tumors have single driver mutation that causes cells to become cancerous. But Acrivon notes that more than 90% of all human cancers don’t have such mutations. Rather than looking for a genetic target, Acrivon measures proteins that are critical to tumor-driving mechanisms. The company contends this proteomics approach could be applicable to the majority of cancers that do not have genetic alterations in the drug target itself. “Our founding vision is that proteomic biomarkers enable direct measurement of the disease-driving mechanisms and allow for accurate matching with drug action, independent of underlying genetic alterations,” Acrivon said in its updated prospectus. The science upon which Acrivon’s technology is based stems from the research of co-founder and CEO Peter Blume-Jensen, whose pharma industry experience includes senior roles at EMD Serono and Merck & Co. In a 2001 article published in the journal Nature, Blume-Jensen and co-author Tony Hunter describe how cancer is driven by dysregulated protein signaling. Acrivon, whose name is derived from the Greek word for “accurate,” formed in 2018. The company’s tech platform, called Acrivon Predictive Precision Proteomics, or AP3, develops tumor biopsy tests that can be used to match a drug to the patients most likely to respond to it. These tests, called OncoSignature, measure for elevated levels of proteins that a tumor depends on and that are specific to biochemical pathways addressed by a drug. Acrivon has used OncoSignature to guide the development of internally discovered drug candidates that are currently preclinical. For OncoSignature’s first test in a clinical trial, the biotech turned to molecule that stalled in the hands of Eli Lilly. The Lilly drug, prexasertib, has a long history with multiple stops. Initially developed under a collaboration between Array Biopharma and Icos, the drug joined Lilly via the pharma giant’s $2.1 billion acquisition of Icos in 2007. The heart of that deal was blockbuster erectile dysfunction drug Cialis; prexasertib was still preclinical at the time. Prexasertib is designed to treat cancer by interfering with a way tumors fix themselves. The rapid and uncontrollable cell growth characteristic of cancer wreaks havoc on cancer DNA. Tumors rely on DNA damage response, a repair mechanism governed by certain proteins. The Lilly drug, which Acrivon has renamed ACR-368, is designed to block CHK1 and CHK2, two proteins that temporarily stop cell replication in order to allow repair of DNA damage. Blocking these proteins prevents those repairs, leading instead to cell death. No CHK1/2 inhibitors have been approved by the FDA yet. Lilly advanced its CHK1/2-blocking drug to multiple Phase 1 and Phase 2 clinical trials but stopped work on the small molecule in 2019. According to Acrivon’s prospectus, Lilly’s Phase 2 tests in ovarian cancer led to an overall response rate of just 12%. Acrivon believes that by identifying likely responders, its technology can lead to better response rates. Acrivon was able to obtain pretreatment samples from a subset of ovarian cancer patients who participated in prexasertib trials run by the National Cancer Institute (NCI) and Lilly. According to the IPO filing, a third-party biostatistician reviewed the trial data and OncoSignature scores and found that using the Acrivon test to identify patients appropriate for the therapy boosted the response rate to 47% in the NCI trial 58% in the Lilly study. Acrivon also said the analysis was able to eliminate patients who are less responsive to the drug, which would have spared them from a treatment that would not help them. Acrivon plans to advance ACR-368 into single-arm Phase 2 studies in ovarian, endometrial, and bladder cancers. Participants in the trials, which the company said could support potential regulatory submissions, will be assigned to subgroups according to their sensitivity to the test drug as determined by OncoSignature. Acrivon acquired prexasertib in 2021 for cheap. According to the IPO filing, the biotech paid $5 million in cash and issued Lilly shares in the company. Acrivon could pay Lilly up to $168 million in milestone payments linked to the progress of the drug, plus royalties from sales if it reaches the market. The agreement also gives Lilly limited first rights to negotiate the reacquisition of the cancer drug. That right expires 45 days after the completion of certain clinical milestones that are not specified in the IPO filing. While ACR-368 gives Acrivon an asset ready for a new slate of mid-stage tests, its preclinical programs address other pathways key to DNA damage response. One addresses a protein called WEE1; the other a protein called PKMYT1. There are competitors developing drugs that address DNA damage response. GSK acquired Sierra Oncology largely due to the promise of myelofibrosis drug momelotinib, but that biotech’s pipeline also includes CHK1 inhibitor SRA737. Phase 2 work on adavosertib, a WEE1-blocking small molecule that AstraZeneca licensed from Merck, was stopped this past summer. But others that have reached the clinic with WEE1 inhibitors include Zentalis Pharmaceuticals, Debiopharm, and Impact Pharmaceuticals. Acrivon’s stock market debut comes nearly one year after it raised $100 million in Series B financing. Prior to the IPO, the biotech raised $119.8 million, according to the filing. Chione is Acrivon’s largest shareholder, owning 18.4% of the company after the IPO. RA Capital Management owns a 7.5% stake. Acrivon reported its cash position was $83.9 million at the end of June. Most of the IPO cash will go toward development of ACR-368. Between $80 million and $90 million is planned for defining the manufacturing processes and product specifications of the drug as well as developing a companion diagnostic, according to the filing. In time, Acrivon plans to test ACR-368 in other cancers based on drug sensitivity assessed by OncoSignature. Those cancers include human papilloma virus positive squamous cell cancer of the head and neck, as well as anal and cervical cancers. The IPO filing states that the company plans to use some of the new capital to start a mid-stage test in patients with HPV-positive tumors. Another $15 million to $20 million is set aside for completing the preclinical testing leading up to an investigational new drug application for at least one of the company’s preclinical programs. The company will use the remaining cash to continue development of the AP3 technology and for other R&D work. Acrivon expects the cash to support the company into the fourth quarter of 2024. Photo by Flickr user FutUndBeidl via a Creative Commons license