RB1

SUZHOU, China, March 14, 2024 /PRNewswire/ -- Kintor Pharmaceutical Limited (" Kintor Pharma", HKEX: 9939.HK), a clinical-stage biotechnology company developing innovative small molecule and biological therapeutics, announces that Kintor and its cooperative partner had published an article named MYC Induces CDK4/6 Inhibitors Resistance by Promoting pRB1 Degradation in a subsidiary journal of Nature—Nature Communications (Impact factor: 16.6). Nature Communications is one of the top journals in biology field and is classified as Q1 in several categories, representing a leading research level in the world. The study shows that target c-Myc molecular glue compound has great potential, which could provide more directions for overcoming resistance issues of CDK4/6 inhibitors in various tumor fields. Issue: This article analyzes the mechanism of c-Myc that induces CDK4/6 inhibitors resistance and introduces A80.2HCl, a promising molecular glue compound developed by Kintor Pharma, to enhance the therapeutic efficacy of CDK4/6 inhibitors. Background: CDK4 and CDK6 (CDK4/6) govern progression through the early G1 phases of the cell cycle, and they have shown profound effects against several solid tumors. CDK4/6 inhibitors (CDK4/6i) have been approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. However, their application to other tumor types and intrinsic resistance mechanisms are still unclear. Existing mechanism studies have shown that the loss of normal RB1 function is the most frequently observed change in cells resistant to CDK4/6i. MYC is one of the most widely investigated oncoproteins that regulates many cellular processes and contributes to tumorigenesis and therapeutic resistance in several different cancer types. This article analyzes the mechanism of MYC that induces CDK4/6 inhibitors resistance by promoting pRB1 degradation and introduces a c-Myc degrader A80.2HCl, a promising molecular glue compound developed by Kintor Pharma, to enhance the therapeutic effectiveness of CDK4/6 inhibitors. Results: High MYC expression drives resistance to CDK4/6i by masking pRB1 High MYC expression reduces pRB1 abundance via proteasomal degradation The E3 ubiquitin ligase KLHL42 interacts with pRB1 and induces pRB1 proteasomal degradation KLHL42 is a transcriptional target of MYC that mediates CDK4/6i resistance Identification of A80.2HCl as a MYC-degrading molecule A80.2HCl potentiates the therapeutic efficacy of CDK4/6 inhibitors Conclusion: High MYC expression drives resistance to CDK4/6i by directly activating the transcription of the E3 ubiquitin ligase KLHL42, which promotes pRB1 ubiquitination and degradation and thus leads to pRB1 protein deficiency A molecule that degrades MYC, A80.2HCl, developed by Kintor Pharma, to abolish MYC when applied at nanomolar levels, rescues pRB1 protein activity, and diminishes MYC-dependent CDK4/6i resistance The combination of CDK4/6i and MYC-degrading molecule A80.2HCl shows an additive effect on killing tumor cells both in vitro and in vivo Full article ： The full article is available in Nature Communications. Download: SOURCE Kintor Pharmaceutical Limited

BEIJING, SHANGHAI and BOSTON, March 1, 2024 /PRNewswire/ -- Jacobio Pharma (1167.HK), a clinical-stage oncology company drugging the undruggable targets, today announced it received IND (Investigational New Drug) approval of its self-developed drug JAB-30300 (P53 Y220C activator) from the FDA of the U.S. Jacobio plans to initiate a Phase I/IIa advanced solid tumors clinical trial in the U.S., to evaluate safety and efficacy of JAB-30300. Jacobio also plans to submit IND in China, and will conduct clinical studies once receives the IND approval. P53 is the single most frequently altered gene in human cancers, with mutations being present in approximately 50% of all invasive tumors. JAB-30300 is an orally bioavailable small molecule activator for the treatment of patients with solid tumors harboring P53 Y220C mutation. Studies shows that, JAB-30300 has shown very high binding affinity to P53 Y220C mutant proteins. Tumor regression was achieved in multiple cancer models covering various tumor types, such as gastric cancer, ovarian cancer, breast cancer and lung cancer. The synergistic effect was found when combined with chemo or oncogenic protein inhibitors which indicates a widely combo potential of JAB-30300. There is only one P53 Y220C activator program in the Phase I clinical stage globally. JAB-30300 is expected to be one of the first P53 Y220C activator to be approved. About Jacobio Jacobio Pharma (1167.HK) is committed to developing and providing new and innovative products and solutions to improve people's health. Our pipeline revolves around novel molecular targets on six major signalling pathways: KRAS, immune checkpoints, tumor metabolism, P53, RB and MYC. We aim for our key projects to be among the top three in the world. Our vision is to become a global leader recognized for our impact in drug R&D together with our partners. Jacobio has R&D centers in Beijing, Shanghai and Boston with our Induced Allosteric Drug Discovery Platform (IADDP) and our iADC Platform. SOURCE Jacobio Pharma

BEIJING and SHANGHAI and BOSTON, Feb. 18, 2024 /PRNewswire/ -- Jacobio Pharma (1167.HK), a clinical-stage oncology company drugging the undruggable targets, today announced it received approval of registrational phase III clinical trial of the combination therapy between its novel KRAS G12C inhibitor glecirasib and novel SHP2 inhibitor JAB-3312. JAB-3312 is the first SHP2 inhibitor entered into phase III study globally in combination with KRAS G12C inhibitor. This approved study in China is a randomized active controlled phase III trial design to evaluate the efficacy and safety of JAB-3312 in combination with glecirasib for first-line non-small cell lung cancer patients with KRAS G12C mutations. The control arm is the current standard treatment for first-line non-small cell lung cancer, which is the combination therapy of PD-1 antibody and chemotherapy. Jacobio initiated clinical trials of SHP2 inhibitors in 2018. Data presented by Jacobio in an oral presentation at the 2023 European Society for Medical Oncology Annual Meeting (ESMO 2023) showed that among 129 patients with non-small cell lung cancer, 58 patients were first-line treatment patients (including 7 dose groups), ORR (objective response rate) was 65.5% (38/58), and the DCR (disease control rate) was 100%. Among them, in the dose group of 800 mg (once daily) glecirasib and 2 mg JAB-3312 (once daily for 1 week on, then 1 week off), the ORR was 86.7% (13/15). This clinical study is continuing to enroll patients. The KRAS G12C inhibitors currently on the market have not been approved as first-line non-small cell lung cancer treatments for KRAS G12C mutations. Jacobio's JAB-3312 and glecirasib are both oral formulations, and the combination therapy is also the first approved Phase III registration clinical trial for dual oral inhibitors in the first-line treatment of non-small cell lung cancer worldwide. About JAB-3312 JAB-3312 is a highly selective SHP2 allosteric inhibitor with best-in-class potential. Jacobio is currently conducting clinical trials of JAB-3312 in monotherapy and combination therapies with glecirasib and other agents in China, the United States and Europe. The phase III study in combination with KRAS G12C inhibitor Glecirasib has been approved by China CDE in Feb 2024. About Glecirasib Glecirasib is a KRAS G12C inhibitor developed by Jacobio. A number of Phase I/II clinical trials of glecirasib are currently ongoing in China, the United States and Europe for patients with advanced solid tumors harboring KRAS G12C mutation. These include a pivotal clinical trial in NSCLC in China; a monotherapy study for STK11 co-mutated NSCLC in the front-line setting, and combination therapy trials with SHP2 inhibitor JAB-3312 in NSCLC and with Cetuximab in colorectal cancer. About Jacobio Jacobio Pharma (1167.HK) is committed to developing and providing new and innovative products and solutions to improve people's health. Our pipeline revolves around novel molecular targets on six major signaling pathways: KRAS, immune checkpoints, tumor metabolism, P53, RB and MYC. We aim for our key projects to be among the top three in the world. Our vision is to become a global leader recognized for our impact in drug R&D together with our partners. Jacobio has R&D centers in Beijing, Shanghai and Boston with our Induced Allosteric Drug Discovery Platform (IADDP) and our iADC Platform. SOURCE Jacobio Pharma