CDK4

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

CAMBRIDGE, Mass., March 8, 2024 /PRNewswire/ -- Regor Therapeutics Group ("Regor"), a clinical-stage global biopharmaceutical company powered by a cutting-edge drug discovery engine and differentiated clinical development pipeline, today announced that its Phase 2 trial of the highly selective oral GLP-1 agonist RGT-075 is initiated in adults with obesity or overweight with weight-related comorbidities and has First Patient First Visit (FPFV) on Mar 08, 2024. The topline results for this Phase 2 trial are expected to be announced in the second half of 2024. "The initiation of the Phase 2 trial marks an important milestone in the development of RGT-075 as we believe it could represent a convenient and potentially meaningful alternative to the currently available weight loss treatments," said Michael Grimm, M.D., Ph.D., Head of Metabolic Diseases at Regor. "RGT-075 is designed to be administered orally once daily as a monotherapy or as part of a potential oral combination treatment for obesity. Phase 1 clinical data showed promising exploratory body weight trends despite short treatment duration," added Dr. Grimm. About the RGT-075 development program The Phase 2 multicenter, randomized, double-blind, placebo-controlled study is designed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of once-daily oral RGT-075 compared with placebo in adult patients with obesity or overweight with weight-related comorbidities. Approximately 60 adult participants with a BMI ≥ 27 kg/m2 and ≤ 45 kg/m2 will be enrolled and randomized to RGT-075 or placebo. The treatment will last 12 weeks; all participants on RGT001-075 will be given RGT-075 once daily (QD) titrated up over 6 weeks, then being maintained with the target dose for 6 weeks. Topline data from the Phase 2 study are expected to be announced in the second half of 2024. About RGT-075 RGT-075 is an oral-available, once-daily, small molecule GLP-1R full agonist discovered and developed by Regor for the treatment of metabolic diseases, such as type-2 diabetes mellitus and overweight/obesity. Regor completed its Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) studies. RGT-075 was safe and clinically well-tolerated in clinical trials completed to date. About Regor Therapeutics Group Regor Therapeutics Group ("Regor") is founded in 2018 by a team of scientists with a proven track record in drug discovery and executive leadership covering full cycle of drug discovery and development. By leveraging its industry-leading core strength in rCARD™ (Computer Accelerated Rational Discovery), Regor has completed 8 PCCs inhouse, with 5 INDs filed, validating Regor's highly efficient ecosystem for accelerated discovery of innovative therapeutic agents. Regor's in-house pipeline encompasses leading assets in metabolism, oncology and auto-immunity, with two leading assets: 1) RGT-075, an orally bioavailable small molecule GLP1R full agonist with best-in-class potential for obesity & beyond; and 2) RGT-419B, a unique CDK4+ inhibitor showing outstanding single agent responses in refractory ER+/HER2- breast cancer patients. With a strong focus on excellence in pharmaceutical research and global competitiveness, Regor aspires to build a world-class innovation engine that promotes a winning culture of scientific excellence, strong teamwork driven by results and delivery with shared accountability and successes. IR Contact: Investor Relations and Communications [email protected] SOURCE Regor Therapeutics Group

By 2030, Pfizer expects about two-thirds of its oncology revenue will be coming from new molecular entities and new indications from existing products. In what CEO Albert Bourla, Ph.D., called an update to a top priority at Pfizer, the company on Thursday systemically laid out its new oncology strategy following the $43 billion acquisition of antibody-drug conjugate specialist Seagen. The company aims to have at least eight blockbuster cancer drugs by 2030, Pfizer’s newly minted chief oncology officer, Chris Boshoff, Ph.D., said during an investor event Thursday as he unveiled the strategic priorities. By then, Pfizer hopes to double the number of patients treated with its innovative cancer medicines from about 2.3 million in 2023. The new plan also sees Pfizer focusing on four main cancer types—breast cancer, genitourinary cancer, blood cancer and thoracic cancers—all of which the company already has commercial products in. “Within these areas, we’re initiating parallel earlier-line trials where the addressable population is the greatest, aiming to both accelerate a new wave of breakthroughs and move approved medicines into earlier lines of treatment,” Boshoff said. Pfizer bought Seagen and devised a new oncology blueprint as top-selling cancer drug Ibrance declines, and as its collaboration revenue from Astellas-partnered Xtandi runs flat. Both drugs are expected to lose market exclusivity in 2027. And the addition of Seagen brings Pfizer to what Boshoff called an inflection point in its position in the oncology field. Pfizer on Thursday stopped short of providing a specific sales projection for the oncology franchise by 2030. The company anticipates “continued strong sales and profit growth in oncology through the end of this decade,” oncology commercial chief Suneet Varma said. By then, about two-thirds of the risk-adjusted oncology revenue will be coming from new molecular entities and new indications from existing products, he added. Before the Seagen deal, Pfizer’s top three cancer drugs—Ibrance, Xtandi and Inlyta—were all small molecules. Now, the New York pharma aims to increase the proportion of biologics in its revenue mix from 6% to 65% by 2030. Touting Pfizer’s ability to boost the former Seagen portfolio, Boshoff pointed to Pfizer’s 10 manufacturing sites that are churning out oncology drugs on three continents, versus one for Seagen, plus six times the capacity for vial volume for antibody-drug conjugate (ADC) production than Seagen alone. Pfizer has commercial presence in over 100 countries, and the combined customer-facing commercial team is triple the size of Seagen’s own, he noted. In breast cancer, Seagen brings over HER2-targeted ADC disitamab vedotin and the tyrosine kinase inhibitor Tukysa. And to carry on Ibrance’s legacy, Pfizer is working on a CDK4 inhibitor called aitrmociclib, which is already in phase 3 development in second-line HR-positive, HER2-negative breast cancer, with a first-line trial planned to start in the second half of this year. Despite growth potential from the new drugs, the Ibrance patent cliff will be so steep that Pfizer expects breast cancer’s contribution to total oncology sales will drop to about 10% by 2030 from about 40% in 2023, Varma told investors during Thursday’s event.  Instead, genitourinary cancer is expected to become Pfizer’s largest oncology franchise, with about 35% contribution. In this area, the combination of Pfizer’s Astellas-partnered Padcev and Merck’s Keytruda is becoming a new standard of care in front-line bladder cancer. And disitamab vedotin, which is already sold in China by RemeGen, is also being tested alongside Keytruda in a phase 3 trial in previously untreated, HER2-expressing bladder cancer. What’s more, Pfizer is also counting on a longer follow-up of overall survival data from the phase 3 TALAPRO-2 trial later this year to potentially expand the combination of its PARP inhibitor Talzenna and Xtandi to a broader prostate cancer population. Besides, the company is looking to launch two phase 3 trials this year in metastatic castration-resistant prostate cancer for mevrometostat. Pfizer recently started a push into blood cancers with the FDA’s approval for Elrexfio, a BCMA-targeted bispecific drug. Again, multiple phase 3 trials are ongoing for the multiple myeloma therapy, including two trials in newly diagnosed patients either as a post-transplant maintenance treatment or for transplant-ineligible patients. Plus, Seagen comes with Adcetris, an established blockbuster for classical Hodgkin lymphoma. As for thoracic cancer, Pfizer has a relatively small presence there today. In lung cancer, Pfizer is working to establish its third-generation ALK inhibitor Lorbrena as the new standard of care in the field. The integrin beta-6-directed ADC sigvotatug vedotin recently entered phase 3 testing in pretreated nonsquamous non-small cell lung cancer, and a readout is expected around 2026 or 2027. In 2023, Pfizer’s oncology sales dropped 3% at constant exchange rates to $11.6 billion, despite a small contribution from the Seagen products in the last few days of 2023. Declines from Ibrance and Xtandi collaboration revenue drove the overall decrease.