MDM2

WATERTOWN, Mass., Oct. 23, 2024 (GLOBE NEWSWIRE) -- Kymera Therapeutics, Inc. (NASDAQ: KYMR), a clinical-stage biopharmaceutical company advancing a new class of small molecule medicines using targeted protein degradation (TPD), today announced that new preclinical data from its innovative TPD platform will be presented across three poster presentations at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics being held October 23-25, 2024, in Barcelona, Spain. The presentations include new data on its preclinical biomarker-based approach for KT-253, its MDM2 degrader. “We have built industry leading knowledge and capabilities that we are leveraging to explore the applicability of our platform, including developing new therapeutic hypotheses to assess the potential of protein degradation to address oncogenic proteins in validated signaling pathways,” said Juliet Williams, PhD, Head of Research, Kymera Therapeutics. “As seen in our presentations at the EORTC-NCI-AACR Symposium, we’ve created a toolbox of integrated approaches to accelerate the discovery and development of transformative degrader medicines.” New data highlights the Company’s research efforts to identify patient populations sensitive to the KT-253 degrader mechanism and define biomarkers associated with an acute apoptotic response in tumors. Using an innovative machine learning framework to develop a predictive signature, the results identified tumor types sensitive to KT-253 that are consistent with preclinical and early clinical findings, including acute myeloid leukemia (AML), neuroendocrine tumors, and subsets of solid tumors with or without neuroendocrine features. KT-253 is in a Phase 1 clinical trial to evaluate its potential as a treatment for solid tumors and hematological malignancies. The Company will also present a poster highlighting its innovative platform capabilities and the case study of the use of targeted protein degradation to provide improved potency and selectivity over traditional small molecule inhibitors for CDK2, a cell cycle regulator and key protein involved in several cancers. Presentations at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics Poster Number: PB283Title: Predictive Markers of Response to the MDM2 Degrader KT-253Presenter: Nancy Dumont, PhD, Director, In Vivo Pharmacology Poster Number: PB032Title: The MDM2 degraders KTX-049 and KT-253 are highly active in wild-type TP53 (WT p53) Merkel cell carcinoma (MCC)Presenter: Yogesh Chutake, PhD, Associate Director, Translational Medicine Poster Number: PB092Title: CDK2 heterobifunctional degraders co-degrade CDK2 and Cyclin E resulting in efficacy in CCNE1-amplified and overexpressed cancersPresenter: Nicholas Kwiatkowski, PhD, Associate Director, Biological Sciences Copies of the EORTC-NCI-AACR poster presentations will be available in conjunction with the conference sessions within the Resource Library section of Kymera's website. About Kymera TherapeuticsKymera is a clinical-stage biotechnology company pioneering the field of targeted protein degradation (TPD) to develop medicines that address critical health problems and have the potential to dramatically improve patients’ lives. Kymera is deploying TPD to address disease targets and pathways inaccessible with conventional therapeutics. Having advanced the first degrader into the clinic for immunological diseases, Kymera is focused on delivering oral small molecule degraders to provide a new generation of convenient, highly effective therapies for patients with these conditions. Kymera is also progressing degrader oncology programs that target undrugged or poorly drugged proteins to create new ways to fight cancer. Founded in 2016, Kymera has been recognized as one of Boston’s top workplaces for the past several years. For more information about our science, pipeline and people, please visit www.kymeratx.com or follow us on X or LinkedIn. Cautionary Note Regarding Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements about our expectations regarding its Targeted Protein Degradation platform and the clinical development and outcomes of KT-253. The words "may," "might," "will," "could," "would," "should," "expect," "plan," "anticipate," "intend," "believe," "expect," "estimate," "seek," "predict," "future," "project," "potential," "continue," "target" and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from any forward-looking statements contained in this press release, including, without limitation, risks associated with: the risk that the results of preclinical studies and clinical trials may not be predictive of future results in connection with current and future clinical trials uncertainties inherent in the initiation, timing and design of future clinical trials, the availability and timing of data from ongoing and future clinical trials and the results of such trials, whether preliminary results of early clinical trials will be indicative of the results of later clinical trials, the ability to successfully demonstrate the safety and efficacy of drug candidates, the timing and outcome of planned interactions with regulatory authorities and other factors. These risks and uncertainties are described in greater detail in the section entitled "Risk Factors" in the most recent Quarterly Report on Form 10-Q and in subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our view as of any subsequent date. We explicitly disclaim any obligation to update any forward-looking statements. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Investor and Media Contact: Justine KoenigsbergVice President, Investor Relationsinvestors@kymeratx.commedia@kymeratx.com857-285-5300

CAMBRIDGE, United Kingdom, Oct. 21, 2024 (GLOBE NEWSWIRE) -- Astex Pharmaceuticals, a pharmaceutical company based in Cambridge, UK, dedicated to the discovery and development of novel small molecule therapeutics for oncology and diseases of the central nervous system, announced today that it will make five key data presentations at the 36th EORTC-NCI-AACR Symposium on molecular targets and cancer therapeutics, 23rd-25th October 2024, Barcelona, Spain. The Astex presentations will focus on its novel small-molecule CBP/p300 HAT domain inhibitor, ASTX528 in preclinical development and its Phase II-ready MDM2 antagonist, ASTX295. Astex data presentations at 36th EORTC-NCI-AACR Symposium, 23rd-25th October 2024, Barcelona TitlePresentationDate/Time/Session Title/PresenterPresentation numberA Novel Small-Molecule CBP/p300 HAT Domain Inhibitor Demonstrates PotentIn VivoActivity and a Favourable Safety Profile in Preclinical SpeciesPosterDate: Wed, 23rdOct 2024Time: 12:00 - 19:00Session Title: Molecular Targeted AgentsPresenter: Gianni Chessari, Astex Pharmaceuticals, UKCatalog #42Presentation #PB030Targeting the Catalytic HAT Domain of CBP/p300 for the Treatment of Hormone-Dependent Breast and Prostate CancersPosterDate: Wed, 23rdOct 2024Time: 12:00 - 19:00Session Title: Molecular Targeted AgentsPresenter: John Lyons, Astex Pharmaceuticals, UKCatalog #73Presentation #PB061From a Preclinical Therapeutic Concept to the Clinic. ASTX295: Discovery of a bone marrow sparing MDM2 antagonistOralDate: Wed, 23rdOct 2024Time: 16:55 -17:15Session Title:Optimising of preclinical models for drug developmentPresenter: Maria Ahn, Astex Pharmaceuticals, UKWorkshop 2Room 113+114Identification of Biomarkers Predictive of Response to ASTX295, a Next-Generation MDM2 Antagonist, in Solid Tumors Carrying Wild-type p53PosterDate: Wed, 23rdOct 2024Time: 12:00 - 19:00Session Title: Molecular Targeted AgentsPresenter: Maria Ahn, Astex Pharmaceuticals, UKCatalog #28Presentation #PB016Pulsatile Induction of the p53 Pathway by MDM2 Antagonist ASTX295 Shows an Enhanced Therapeutic Indexin vivoPosterDate: Thu, 24thOct 2024Time: 9:00 - 17:30Session Title: Translational StudiesPresenter: Andrea Biondo, Astex Pharmaceuticals, UKCatalog #289Presentation #PB277 ASTX528 - CBP/p300 HAT Domain Inhibitor - Preclinical ASTX528 is a novel small molecule CBP/p300 HAT domain inhibitor with potent in vivo activity and a favourable safety profile in preclinical species that was discovered by Astex using its proprietary fragment-based drug discovery approach. CREB binding protein (CBP) and its paralog, EP300 (p300), are lysine acetyltransferases and transcriptional cofactors implicated in human cancers. Dose-limiting tolerability issues have been observed with dual CBP/p300 bromodomain (BRD) inhibitors, which may limit their clinical utility. We hypothesised that a dual inhibitor targeting the histone acetyltransferase (HAT) domain may improve the therapeutic window. Our presentations will describe the effects of CBP/p300 HAT domain inhibition in preclinical models of AR- and ER-driven cancers and the characterisation of ASTX528, a potent, fragment-derived CBP/p300 HAT domain inhibitor with a low predicted human dose and promising preliminary toxicity evaluation. Astex is interested in discussing the further development of ASTX528 with potential partners. ASTX295 – Bone Marrow-Sparing MDM2 Antagonist, Phase II-ready ASTX295 is an oral, potent inhibitor of the p53-MDM2 protein-protein interaction that was discovered by Astex using its proprietary structure-based drug design approach. The compound was specifically designed to overcome the on-target toxicity seen in the first generation MDM2 antagonist compounds which have shown dose-limiting haematological toxicities in the clinic. In contrast, ASTX295 is a potent MDM2 antagonist with a clean CYP/hERG profile and a shorter human half-life allowing for pulsatile pathway modulation while avoiding myelosuppression. ASTX295 therefore has bone-marrow sparing characteristics which permit a differentiated safety profile. ASTX295 was discovered by Astex in collaboration with the Cancer Research UK Drug Discovery Unit at Newcastle University. Astex has an exclusive license to research, develop and commercialise ASTX295 under its drug discovery alliance agreement with Newcastle University and Cancer Research Technology Limited. About Astex Pharmaceuticals Astex is a leader in innovative drug discovery and development, committed to the fight against cancer and diseases of the central nervous system. Astex is developing a proprietary pipeline of novel therapies and has several partnered products being developed under collaborations with leading pharmaceutical companies. Astex is a wholly owned subsidiary of Otsuka Pharmaceutical Co. Ltd., based in Tokyo, Japan. For more information about Astex Pharmaceuticals, please visit: http://www.astx.com For more information about Otsuka Pharmaceutical, please visit: https://www.otsuka.co.jp/en/ Contact At the Company:Jeremy CarmichaelSVP Corporate DevelopmentHead of Business DevelopmentTel: +44(0)1223 226289Email: jeremy.carmichael@astx.comFor Media Enquiries:Sue CharlesCharles ConsultantsTel : +44(0)7968 726585Email: sue@charles-consultants.com

即使在氧充分的条件下（有氧糖酵解/Warburg效应），癌细胞上调葡萄糖的糖酵解途径形成乳酸，这个过程被认为是恶性肿瘤的标志。代谢活跃的癌细胞导致营养消耗、缺氧、酸性、有毒的代谢物富集的肿瘤微环境，抑制免疫系统。 肿瘤细胞代谢与肿瘤微环境 （Nat Rev Cancer . 2020 Sep;20(9):516-531） 本文简介肿瘤细胞代谢调节的5条信号通路。 其他代谢相关文章，请点击下面链接阅读 23种代谢产物与肿瘤免疫 T细胞代谢与功能的关系 1. Hippo Pathway Hippo通路控制细胞增殖、器官大小和组织稳态。它由MAPK家族、MST1/2、LATS1/2以及转录共激活因子YAP和TAZ组成。 当该通路被激活时，上游信号磷酸化并激活MST1/2和LATS1/2，从而磷酸化YAP/TAZ。因此，YAP/TAZ通过14-3-3蛋白被隔离在细胞质中，并被E3连接酶β-TRCP降解。 Annu Rev Pathol. 2021 January 24; 16: 299–322 然而，当Hippo信号通路关闭时，YAP/TAZ易位到细胞核，与转录增强相关域(TEAD)转录因子结合，诱导致癌靶基因的表达。 Hippo通路受到广泛的上游调控因子的调控，包括细胞-细胞接触、来自周围环境刺激、Wnt信号传导、GPCR-配体相互作用和各种细胞应激条件。 YAP/TAZ促进糖酵解和谷氨酸代谢 YAP/TAZ活性在许多类型的癌症中都是过度活跃。hHippo通路作为细胞生长的主调节因子，参与了多种代谢过程。YAP/TAZ活性通过直接和间接提高糖酵解酶活性来促进糖酵解。特别是，YAP/TAZ的活性增加了TEAD对GLUT3的表达，并通过FOXC2诱导了HK2的表达。YAP/TAZ还通过Hedgehog信号通路促进LncRNABCAR4的表达，上调HK2和PFKFB3。YAP/TAZ增强谷氨酰胺代谢，增加乳腺癌细胞中谷氨酰胺转运体SLC1A5和SLC7A5的表达。YAP/TAZ和TEAD通过表达氨基酸转运体上调谷氨酰胺和氨基酸代谢。YAP/TAZ诱导谷氨酰胺酶和转氨酶的表达，包括GOT1和PSAT1，它们产生NEAAs和TCA循环中间体。YAP/TAZ积累脂质，直接调节胆汁酸成分，从而增强癌细胞的转移潜能。 葡萄糖增强YAP/TAZ的活性 细胞周期进程和细胞增殖由营养物质浓度决定。葡萄糖代谢对YAP/TAZ活性有显著影响。高糖水平增加了HSP的葡萄糖通量，产生用于糖基化的UDP-GlcNAc。因此，丰富的葡萄糖诱导YAP O-GlcNAcylation，干扰LATS和βTrCP的相互作用，进而增强YAP/TAZ的活性。在胰腺癌和肝癌中，YAP被O-GlcNAcylation过度激活。 LATS2的糖基化通过干扰乳腺癌中LATS2和MOB1的相互作用来抑制其活性。相反，葡萄糖剥夺诱导的能量应激通过hippo依赖和非依赖的机制抑制YAP/TAZ活性。能量传感器AMPK随着ATP的减少而被激活。AMPK直接磷酸化YAP的丝氨酸61和丝氨酸94，从而阻断YAP-TEAD的相互作用。AMPK通过AMOTL1磷酸化和激活间接抑制YAP。 外部激素水平可以调节Hippo通路。脂质激素，如溶血磷脂酸和鞘氨醇-1-磷酸，通过GPCRs抑制该通路，肽激素胰高血糖素增加血糖水平，通过cAMP和PKA激活Hippo通路。 脂肪增强YAP/TAZ的活性 亚细胞脂质成分也可以调节Hippo通路激酶。SREBP是Hippo通路的上游调控因子。当SREBP被激活时，甲羟戊酸途径增强了RhoAGTPase的香叶酰化。RhoA是一个f-actin的细胞骨架调节因子，而f-actin是一个成熟的LATS激酶的上游因子。因此，癌细胞中脂肪酸代谢的增加会异常激活RhoA，并通过抑制LATS来增强YAP/TAZ的活性。 有趣的是，YAP/TAZ在血液系统恶性肿瘤中几乎不表达，而YAP的强制表达已被证明可以介导肿瘤抑制功能。 2. PI3K-AKT/mTOR Pathway 在正常细胞中，细胞的增殖和合成代谢受到外部生长因子（如胰岛素和激素）的微妙调节，PI3K-AKT-mTOR通路是其中一条重要通路。 PI3K/AKT信号通路调节代谢酶。在被胰岛素激活后，AKT通过磷酸化GSK3来抑制糖原合成途径。PI3K/AKT通过代谢酶的翻译后修饰（如磷酸化、糖基化）直接或间接上调糖酵解。例如，AKT磷酸化并激活AS160蛋白，从而增强了GLUT的膜运输。AKT通过抑制磷酸化直接抑制TXNIP，通过抑制内吞作用增加GLUT1/4的膜表达。 AKT还提高了糖酵解酶的效率。AKT通过增加HK2的线粒体整合来磷酸化并激活HK2。AKT使PFKFB磷酸化；这种变化催化果糖-6-磷酸到F-2,6-BP，从而提高糖酵解。AKT信号通路也通过HIF-1α转录因子促进糖酵解。HIF-1激活一些糖酵解组分，包括GLUT。HIF-1诱导LDH促进乳酸分泌和有氧糖酵解。 PI3K/AKT信号通路上调谷氨酰胺和脂肪酸代谢。AKT通过mTORC1增加Myc的翻译，并通过GSK3和FOXO3A抑制Myc的降解。由于MYC调节谷氨酰胺代谢，MYC的激活增加了细胞氮的供应。因此，AKT促进了核苷酸的合成。癌细胞需要从头脂质合成来维持和供应持续的无限细胞分裂所需的膜成分。AKT通过直接磷酸化脂质合成的第一个酶ACLY，影响脂质的新生生物合成过程，从而提高酶的效率。AKT通过ACLY调控增加各种癌症类型中的组蛋白乙酰化 AKT诱导的mTORC1激活增强了SREBP家族的翻译和切割加工。AKT介导的GSK3抑制进一步阻止了SREBP1的降解。因此，了解通过PI3K/AKT信号通路的代谢重编程将阐明PI3K抑制剂对癌症治疗的有效治疗替代方案。 3. Myc Pathway 转录因子c-Myc通过MAX调控基因表达，是癌细胞中最过度活跃的基因之一，位于生长相关信号通路(如EGFR、AKT和GPCRs)的交叉点。 Myc调节与葡萄糖、谷氨酰胺和脂肪酸代谢相关的基因的表达。Myc通过上调糖酵解和谷氨酰胺水解来增强癌细胞的代谢重。Myc诱导许多糖酵解酶(如GLUT、HK2和PFK)，它们催化糖酵解过程相应步骤。 MYC癌基因的激活驱动谷氨酰胺的优先代谢向TCA循环添补反应（Anaplerosis）和随后的氧化磷酸化。MYC癌基因表达的缺失增加了线粒体代谢对葡萄糖的依赖。 4. p53 Pathway P53是最著名的肿瘤抑制基因之一，它影响细胞过程，包括凋亡、细胞周期进程和代谢。p53在细胞应激条件下被激活，如DNA损伤和营养剥夺。根据应激源的类型和强度，它决定了是发生适应还是细胞死亡。p53在转录、翻译和翻译后水平上被调节。p53的稳定性受E3连接酶MDM2的调控。 AMPK磷酸化，乙酰化，从而在能量应激条件下稳定p53。通过上调MDM2来促进p53的降解，p53诱导一个负反馈回路来维持稳态。 p53调节代谢（Cancers 2021, 13, 133） P53减少有氧糖酵解，上调线粒体分解代谢过程，包括脂肪酸氧化(FAO)和OXPHOS；p53转录抑制GLUT1和GLUT4的表达，抑制葡萄糖摄取；抑制TCA循环；增加脂肪酸氧化；增加氧化磷酸化（OXPHOS），积累NADH和FADH2。 5. LKB1/AMPK Pathway AMPK是一种保守性良好的能量传感激酶。AMPK抑制合成代谢途径（脂肪酸合成、mTOR途径），促进分解代谢（糖酵解、Krebs循环、磷酸戊糖途径、脂肪酸氧化和自噬）的细胞过程。因此，AMPK的激活允许细胞承受细胞能量应激条件。 与其他代谢蛋白不同，AMPK的调控依赖于AMP和ADP的细胞浓度，但独立于其他代谢中间体。AMP/ATP比值的增加导致AMP相互作用，随后是AMPK的构象变化。在癌症的背景下，应激环境下的AMPK激活，包括缺氧和能量或营养剥夺，赋予了各种癌症的应激抵抗特性。  *红色箭头（激活上调）（Oxid Med Cell Longev . 2019 Oct 31;2019:8730816.） AMPK是一种致癌蛋白还是肿瘤抑制蛋白仍有待确定。在临床环境中，AMPK激活剂，包括2型糖尿病药物二甲双胍和AICAR，被用于抑制癌细胞增殖；然而，AMPK也通过促进原蛋白抗性、迁移和转移作为致癌蛋白。 ACC是AMPK的一个成熟的靶点。ACC在脂肪酸从头合成过程中，ACC介导乙酰辅酶A转化为丙二酰辅酶A。AMPK通过抑制ACC磷酸化来减少ATP的消耗。AMPK降低的脂肪酸合成通量降低了NADPH的消耗。为了满足细胞对脂质代谢物的需求，AMPK通过CD36和其他脂质转运体上调脂肪酸的摄取来维持脂质稳态。 蛋白质翻译是高度耗能的，并使用多种合成代谢途径，包括PPP和谷氨酰胺水解。AMPK通过抑制mTORC1和翻译机制，允许癌细胞适应恶劣的营养条件，如葡萄糖剥夺。 主要参考文献 Jordan H. Driskill et al，The Hippo Pathway in Liver Homeostasis and Pathophysiology. Annu Rev Pathol. 2021 January 24; 16: 299–322 Robert D. Leone and Jonathan D. Powell, Metabolism of immune cells in cancer, Nat Rev Cancer . 2020 Sep;20(9):516-531 Tambay, V.; Raymond, V.-A.; Bilodeau, M. MYC Rules: Leading Glutamine Metabolism toward a Distinct Cancer Cell Phenotype. Cancers 2021, 13, 4484 : Lahalle, A.; Lacroix, M.; De Blasio, C.; Cissé, M.Y.; Linares, L.K.; Le Cam, L. The p53 Pathway and Metabolism: The Tree That Hides the Forest. Cancers 2021, 13, 133 Francesco Ciccarese et al. LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective,Oxid Med Cell Longev . 2019 Oct 31;2019:8730816.