CDK1

- NKT3964 is a first-in-class, highly potent and selective CDK2 degrader, and causes prolonged CDK2 pathway inhibition without cyclin E accumulation - NKT3964 is designed to treat patients with cyclin E driven cancers WILMINGTON, Del.--(BUSINESS WIRE)--NiKang Therapeutics ® Inc. (“NiKang”) is a clinical stage biotech company focused on developing innovative small molecule oncology medicines to bring transformative therapies to patients in need. The company announced today the unveiling of NKT3964 at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (“Triple Meeting”) during a Poster Spotlight Session. The conference is being held October 23-25, 2024, in Barcelona, Spain. NKT3964 is a first-in-class, orally bioavailable small molecule CDK2 degrader that selectively degrades CDK2, demonstrating high specificity over CDK1 and other CDK family members. Its high potency and unique mechanism of action result in sustained inhibition of CDK2 pathway without causing cyclin E accumulation. NKT3964 is designed to treat patients with aberrant CDK2/cyclin E pathway activation, including those with ovarian, endometrial, gastric and HR+HER2- breast cancers. NiKang has initiated a phase 1, open-label, dose escalation study of NKT3964 as a single agent. This first-in-human study (NCT06586957) is designed to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity to determine the preliminary recommended dose for expansion of NKT3964 in adults with advanced or metastatic solid tumors. “We are excited to share the discovery of NKT3964, a first-in-class oral CDK2 degrader at this year’s Triple Meeting,” said Zhenhai Gao, Ph.D., co-founder, president, and CEO of NiKang. “This is the second of three programs targeting the cell cycle (CDK2 inhibitor NKT3447, CDK2 degrader NKT3964, and a CDK2/4 selective dual degrader) that we have advanced to the clinic. We believe CDK2 plays a critical role in driving tumor growth. Recent clinical data presented at ESMO further validates CDK2 as a key oncology target. We are developing a cutting-edge portfolio of CDK2 and CDK2/4 degraders that can achieve sustained CDK pathway inhibition while avoiding paradoxical cyclin E increase. Our multi-pronged approach allows us to thoroughly and deeply interrogate this pathway. We look forward to exploring NKT3964’s potential in treating patients with advanced or metastatic solid tumors.” Poster Presentation Details: Title: Discovery of NKT3964: a first-in-class, highly potent and selective, orally bioavailable CDK2 PROTAC degrader for cancer therapy Presenter: Jianlin Geng, Ph.D. Abstract Number: PB002 Session: Posters in the Spotlight Date/Time: 2:00 p.m.-2:40 p.m. CEST on October 24, 2024 About NKT3964 NKT3964 is a first-in-class, highly potent and selective, orally bioavailable CDK2 PROTAC degrader, causing prolonged CDK2 pathway inhibition without cyclin E accumulation. It has the potential to maximally inhibit the CDK2 pathway, fully harnessing the therapeutic benefits of CDK2 inhibition. NKT3964 is currently under evaluation in a Phase 1 clinical study in advanced or metastatic solid tumors as a single agent (NCT06586957). About NiKang Therapeutics NiKang Therapeutics is a clinical-stage biotech company focused on discovering and developing innovative small molecule oncology medicines to bring transformative therapies to patients in need. Our target selection is driven by deep insight into disease biology and molecular pathways. Our discovery approach is informed by target structure biology and capitalizes on structure-based drug design. The successful implementation of our strategy enables us to rapidly and efficiently discover and advance proprietary drug candidates with the most desirable pharmacological features into clinical studies. We have successfully advanced three programs into clinical trials, including NKT2152 (HIF2α), NKT3447 (CDK2), and NKT3964 (CDK2). For more information, please visit Contacts Kelsey Chen Chief Financial and Operating Officer IR@nikangtx.com

– Preclinical data demonstrate that inhibiting the p300 KAT domain reactivates p53 in HPV-driven tumors resulting in anti-tumor activity –SAN MATEO, Calif., and CAMBRIDGE, Mass., Oct. 23, 2024 (GLOBE NEWSWIRE) -- Kronos Bio, Inc. (Nasdaq: KRON), a company dedicated to developing small molecule therapeutics that address cancers and autoimmune diseases driven by deregulated transcription, today announced preclinical data from its p300 KAT inhibitor program for human papillomavirus (HPV)-driven tumors at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. Kronos Bio is exploring the utility of its p300 KAT inhibitor, KB-9558, for HPV-driven tumors. In the presentation, the authors show that the HPV genome preferentially integrates into transcriptionally active regions in the human genome where it becomes dependent on p300 to drive expression of its E6 and E7 oncogenes. It is widely recognized that elevated transcription of HPV E6 and E7 genes promotes degradation of tumor suppressors p53 and Rb. Importantly, inhibition of p300 KAT activity was highly selective in repressing the transcription of E6 and E7, which in turn led to restoration of the p53 and Rb pathways and drove anti-tumor effects through apoptosis and inhibition of uncontrolled tumor cell growth. "Continued expression of certain viral genes, especially E6 and E7, plays a critical role in tumor growth and progression of HPV-driven tumors, including head & neck, cervical, and other anogenital cancers. Importantly, there are no approved targeted therapies that inhibit E6 and E7,” said Charles Lin, Ph.D., chief scientific officer of Kronos Bio. "While this is early-stage research, given the ability of p300 KAT inhibition to target E6 and E7 and restore tumor suppressor pathways, we believe this p300 KAT inhibitor has the potential to be a remarkable and unique approach toward ensuring that fewer people suffer from HPV-driven cancer." In the presentation titled, "Oncogenic human papillomavirus hijacks p300 to drive viral transcription, creating a therapeutic vulnerability that can be exploited with selective p300/CBP catalytic inhibitors", the authors describe the experiments that led to the following key findings: HPV integrates into the human genome at specific locations where p300 regulates transcriptionp300 inhibition demonstrated specific and potent reduction of expression of HPV oncogenes E6 and E7, both at the RNA and protein levelLoss of E6 and E7 led to restoration of p53 and Rb tumor suppressor pathways which led to the upregulation of p53 activated genes (e.g., CDKN1A) and downregulation of Rb repressed genes (e.g., CDK1)Re-expression of E6 and E7 from an exogenous lentiviral vector where viral oncogene transcription is not mediated by p300 KAT activity reversed the effects of p300 KAT inhibition on p53 restoration and anti-tumor effectsThese findings support the potential of KB-9558, a p300 KAT inhibitor, to treat HPV-driven tumors given its potential to suppress E6 and E7 expression and restore the p53 pathway The poster presentation will take place on October 24, 2024, and is currently available under the Publications section of the Kronos Bio website. About Kronos BioKronos Bio is a clinical-stage biopharmaceutical company dedicated to developing small molecule therapeutics that address deregulated transcription, a hallmark of cancer and autoimmune disease. Our proprietary discovery engine decodes complex transcription factor regulatory networks to identify druggable cofactors. We screen for and optimize small molecules that target these cofactors in a disease-specific context. Kronos Bio has a pipeline of three drug candidates. Istisociclib (KB-0742) is currently enrolling ovarian cancer patients in a Phase 1/2 clinical trial. Preclinical candidate KB-9558 is being developed for multiple myeloma and HPV-driven tumors. KB-7898 is Kronos Bio’s first autoimmune development candidate and has a target indication of Sjögren’s disease. Kronos Bio is based in San Mateo, Calif., and has a research facility in Cambridge, Mass. For more information, visit https://www.kronosbio.com or follow the Company on LinkedIn. Forward-Looking StatementsStatements in this press release that are not statements of historical fact are forward-looking statements for purposes of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. The press release, in some cases, uses terms such as “anticipate,” “believe,” “could,” “expect,” “plan,” “will,” “may,” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. Forward-looking statements include statements regarding Kronos Bio’s intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things, KB-9558’s ability to potentially treat HPV-driven tumors; the potential of Kronos Bio’s product candidates, pipeline and its proprietary discovery engine; and other statements that are not historical fact. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, including, without limitation: changes in the macroeconomic environment or competitive landscape that impact Kronos Bio’s business; whether Kronos Bio will be able to progress its preclinical pipeline on the timelines anticipated, including due to risks inherent in the development of novel therapeutics; the risk that results of preclinical studies, early clinical trials (including preliminary results) and pharmacokinetic modeling are not necessarily predictive of future results; and risks associated with the sufficiency of Kronos Bio’s cash resources and need for additional capital. These and other risks are described in greater detail in Kronos Bio’s filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in its Quarterly Report on Form 10-Q for the quarter ended June 30, 2024, filed with the SEC on August 8, 2024. Any forward-looking statements that are made in this press release speak only as of the date of this press release and are based on management’s assumptions and estimates as of such date. Except as required by law, Kronos Bio assumes no obligation to update the forward-looking statements whether as a result of new information, future events or otherwise, after the date of this press release.

On September 30, Genentech, a division of Roche, entered into a major agreement with Rueger, with Genentech successfully acquiring Rueger's portfolio of next-generation CDK inhibitors for $850 million in upfront cash and other potential milestone payments. This transaction not only refreshes the down payment record for the foreign authorization of domestic molecules, but also marks a new milestone in the cooperation between the two sides. The previous record was held by Benefi Tianheng's agreement with BMS for the BL-B01D1 molecule, which was valued at $800 million. It is worth noting that the transaction between Benefi Tianhengand BMS only involves a single molecule BL-B01D1, which is already in the late clinical stage, and both parties share the subsequent overseas clinical costs. The collaboration with Genentech builds on a broader portfolio of next-generation CDK inhibitors, which is expected to include the Phase I CDK2/4/6 inhibitor RGT-419B and the preclinical CDK2 inhibitor QR-6401. Under the terms of the agreement, Genentech will be responsible for the global clinical development, manufacturing and commercialization of these products after the end of the existing Phase 1 clinical phase. Recently, the field of CDK inhibitors has become a hot spot pursued by many companies. In addition to Genentech, Beigene also announced the introduction of ETX-197, a CDK2 inhibitor from Onsun Pharma, at the end of November last year. Although the amount of the upfront payment was not disclosed, taking into account potential future milestone payments and sales sharing, the total value of the deal is up to $1.33 billion. With some generic CDK4/6 inhibitors entering the market in bulk, some investors are questioning whether the competitive landscape on the CDK inhibitor circuit has reached saturation. However, leading companies such as Roche and Beigene are still actively developing next-generation CDK inhibitors, which has a profound scientific and commercial logic behind it. CDKs (cyclin-dependent kinases), as an important member of the serine/threonine protein kinase family, play a crucial role in cell cycle regulation. CDK family targets are mainly divided into two categories: one is involved in cell cycle regulation and related mitosis, such as CDK1, 2, 4, 6; The other group is mainly involved in transcriptional regulation and phosphorylation of RNA polymerase II, such as CDK7, 8, 9, 11. Among them, CDK4/6 and CDK2 have attracted much attention due to their important roles in the development of tumors. CDK4/6 is a key condition protein in the human cell division and proliferation cycle, which can trigger the cell cycle transition from the growth phase (G1 phase) to the DNA replication phase (S phase). In many cancer cells, CDK4/6 is overexpressed, which promotes the disorderly proliferation of cancer cells through over-phosphorylation and inhibition of Rb protein. Therefore, CDK4/6 inhibitors can inhibit the proliferation of tumor cells by blocking the cell growth cycle in the G1 phase. CDK2 plays a key role in the early phase of DNA synthesis (G1 phase) and the phase of DNA synthesis (S phase) of the cell cycle, and its overexpression is closely related to the abnormal regulation of the cell cycle and the excessive proliferation of cancer cells. From a market perspective, breast cancer, as the world's largest malignant tumor (accounting for about 24.5% of all malignant tumors), provides a broad application space for CDK inhibitors. In particular, the large population of HR+/HER2- advanced breast cancer patients (about 60%-70%) makes endocrine therapy combined with CDK4/6 inhibitors a first-line treatment in this area. This also explains why CDK4/6 inhibitors can occupy an important position in the treatment of breast cancer and create a large drug market size. Despite the proliferation of blockbuster drugs in recent years, existing and older CDK4/6 inhibitors inevitably have several shortcomings, the most significant of which are drug toxicity and resistance. First, in terms of toxicity, hematotoxicity is the most common side effect of CDK4/6 inhibitors. These inhibitors inhibit cell proliferation by blocking the cell cycle, thus killing rapidly dividing cells, but this mechanism also leads to myelosuppression, which reduces blood cell production. Specifically, neutropenia, leukopenia, anemia, and thrombocytopenia are the most common hematological toxic side effects of commercialized CDK4/6 inhibitors. In addition, CDK4/6 inhibitors may also cause gastrointestinal adverse reactions, which should not be ignored. Second, in terms of drug resistance, although CDK4/6 inhibitors have achieved remarkable results in improving disease control in HR+/ HER2-breast cancer patients, 15-20% of patients still develop primary resistance to the drug at the beginning of treatment, while 30-40% of patients develop resistance gradually over the course of treatment. The mechanisms of drug resistance are complex and diverse, including but not limited to ESR1 gene mutation, upregulation of PI3K/AKT/mTOR signaling pathway, and BRCA2 gene mutation. In view of the influx of generic drugs of the older generation of CDK4/6 inhibitors and the urgent need to solve the existing toxicity and drug resistance problems, the new generation of CDK inhibitors ushered in more development opportunities. The RRT-419B that Roche is concerned about is a new generation of CDK2/4/6 small molecule inhibitor developed by Rueger Pharmaceutical. The drug is not commercially available worldwide, and its kinase activity profile has been optimized to target "better" safety and resistance CDK inhibitors from the outset. Regal's RRT-419B shows unique ingenuity in both design ideas and drug mechanisms, and has achieved preliminary validation of ideas in existing breast cancer clinical data. Unlike existing commercialized CDK inhibitors, which mainly inhibit subtypes 4 and 6, RGT-419B aims to reduce the occurrence of resistance to existing CDK4/6 inhibitors by increasing the inhibition of CDK2 subtypes, thereby achieving long-term efficacy. When CDK4/6 activity is inhibited, expansion of Cyclin E and activation of the oncogene MYC lead to up-regulation of MYC and activation of CDK2. CDK2-CyclinE, as a compensatory pathway, phosphorylates Rb, thereby releasing E2F transcription factors and promoting tumor cell proliferation. This process is the key to the development of acquired resistance to CDK4/6 inhibitors. Preliminary data from overseas studies such as Pfizer's CDK2 inhibitor PF-07104091 also revealed an association between CDK2 activation and acquired resistance to CDK4/6 inhibitors. In December 2023, Rueger presented the latest clinical data for RGT-419B at the SABCS Conference. The drug performed well in a Phase 1a clinical trial of monotherapy in 12 patients with HR+/ HER2-metastatic breast cancer receiving CDK4/6is and ET progression: three patients achieved partial response (PR) and continued treatment; Six patients received RGT-419B for more than 24 weeks; The drug was safe and well tolerated, no dose-limiting toxicity occurred, and no patient stopped treatment due to adverse events. Given the huge potential of next-generation CDK inhibitors in second-line breast cancer monotherapy, and the successful performance of commonly used second-line endocrine drugs such as fluvestrant in the market (such as the peak sales of $1.028 billion for fluvestrant in 2018), the global market for next-generation CDK inhibitors is expected to reach at least $2-3 billion. That is one of the reasons Roche is willing to bet so heavily. Faced with such a broad market prospect, many domestic pharmaceutical companies have also devoted themselves to the research and development of a new generation of CDK2/4/6 inhibitors or CDK2 inhibitors. One kind of large pharmaceutical companies further expand the development of CDK2 inhibitors on the basis of CDK4/6 inhibitor layout, such as Hengrui Pharmaceutical and First Sound Pharmaceutical; The other category is the first to enter the CDK inhibitor track of Biotech or big pharmaceutical companies such as Ruge Pharmaceutical, Stone pharmaceutical Group and Homology Kang Pharmaceutical. These companies are advancing the CDK inhibitor field and competing for future market share through continuous research and development and innovation. Although most of the CDK2/4/6 inhibitors that have entered the clinical stage in China are still in the early clinical stage, and most of them have not yet been validated by clinical data, it can be observed from the transaction cases of Regal Medicine and Beigene that these two authorized molecules have been deeply optimized by AI technology. From the information that has been made public, the AI pharmaceutical platform has played a key driving role in Genentech/Regal Pharma's RGT-419B and Beigene/Angsen Pharma's ETX-197 project. It is worth noting that the high degree of similarity among CDK family members makes the development of highly selective CDK2 inhibitors a great challenge. If the molecular selectivity is insufficient, it may lead to off-target phenomenon, which will affect the efficacy and safety of the drug. With the assistance of the AI model Kinetic EnsemNET, Onson has successfully identified a key hidden dynamic binding pocket of CDK2, thereby developing a potential BIC CDK2 candidate with high activity, high selectivity and a wide therapeutic window, which lays the foundation for its subsequent collaboration with Beigene. On the other hand, Ruge Pharmaceutical relied on its self-developed AI-assisted new drug research and development platform CARD to achieve the best selective screening of multiple CDK targets, and successfully promoted the clinical trial process of RGT-419B in the United States. From the licensing trend of CDK inhibitors, we can take a lesson: in the future, investors may need to pay more attention to the investment opportunities of Biotech companies that use AI technology to solve the difficult drug target or hot target iterative drug development challenges.