The nomination of novel Kv1.3 inhibitor DPT0218 for the treatment of various immunological diseases including IBD and AD. • DPT0218 is a gut-restricted, highly potent and selective Kv1.3 inhibitor with excellent in vivo efficacy and safety profile in preclinical studies.

提名新型Kv1.3抑制剂DPT0218用于治疗包括IBD和AD在内的各种免疫疾病。•DPT0218是一种肠道限制性，高效和选择性Kv1.3抑制剂，在临床前研究中具有优异的体内疗效和安全性。

This project further validates the capabilities of DP Technology's drug design platform RiDYMO®.

该项目进一步验证了DP技术的药物设计平台RiDYMO®的功能。

BEIJING, Jan. 30, 2024 /PRNewswire/ -- DP Technology, an 'AI for Science' new paradigm-driven company, today announced the nomination of DPT0218, a novel small molecule targeting Kv1.3, as a preclinical candidate compound for the treatment of various autoimmune diseases, including Inflammatory Bowel Disease (IBD) and Atopic Dermatitis (AD)..

北京，2024年1月30日/PRNewswire/-DP Technology，一家“人工智能科学”新范式驱动的公司，今天宣布提名DPT0218（一种靶向Kv1.3的新型小分子）作为治疗各种自身免疫性疾病（包括炎症性肠病（IBD）和特应性皮炎（AD））的临床前候选化合物。。

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The voltage-gated potassium channel Kv1.3 is known to be crucial for maintaining the membrane potential required for the induction of inflammatory responses[1] because Kv1.3 inhibition reduces calcineurin mediated immune cell activation and proliferation[2]. Inhibition of Kv1.3 therefore offers a potential opportunity to specifically impair inflammatory immune cell activity and proliferation, including in antigen-activated T cells.

已知电压门控钾通道Kv1.3对于维持诱导炎症反应所需的膜电位至关重要，因为Kv1.3抑制减少了钙调神经磷酸酶介导的免疫细胞活化和增殖。因此，抑制Kv1.3提供了特异性损害炎症免疫细胞活性和增殖的潜在机会，包括在抗原激活的T细胞中。

Previously, Eli Lilly and Company (Lilly) made an initial payment of $60 million to D. E. Shaw Research (DESRES), with potential development and commercial milestone payments of up to $475 million for DES-7114, a lead compound of the Kv1.3-targeted therapeutics program..

此前，礼来公司（礼来）向D.E.Shaw Research（DESRES）支付了6000万美元的首期付款，其中DES-7114（Kv1.3靶向治疗计划的先导化合物）的潜在开发和商业里程碑付款高达4.75亿美元。。

Recently, the activity of T cells has become a compelling intervention point in IBD[3]. Long-lived memory T-cell populations, particularly tissue resident subsets, may contribute to the chronicity of IBD and represent a potential target for therapy[4]. Kv1.3 expression was elevated in PBMCs from UC patients and correlated with the prevalence of Th1 and Th2 T cells.

最近，T细胞的活性已成为IBD（3）中引人注目的干预点。长寿记忆T细胞群，特别是组织驻留亚群，可能有助于IBD的慢性，并代表潜在的治疗靶点（4）。UC患者PBMC中Kv1.3表达升高，并与Th1和Th2 T细胞的患病率相关。

Kv1.3 expression was also detected on T cells from biopsies of UC patients[5]..

在UC患者活检的T细胞上也检测到Kv1.3表达。。

It is estimated that there are at least 8 million IBD patients worldwide, of which more than 5 million in Europe and the U.S. The global market for autoimmune drugs is projected to reach $140 billion by 2028, with IBD medications accounting for $28 billion, representing 20% of the market share.DPT0218 is a potential 'best-in-class' highly selective Kv1.3 inhibitor with a novel scaffold.

据估计，全球至少有800万IBD患者，其中欧洲和美国有500多万。到2028年，全球自身免疫药物市场预计将达到1400亿美元，IBD药物占280亿美元，占市场份额的20%。DPT0218是一种具有新型支架的潜在“同类最佳”高选择性Kv1.3抑制剂。

It has shown positive results in preclinical animal models of various autoimmune diseases such as IBD and AD. The compound exhibits sub-nanomolar potency and has achieved over 2000-fold selectivity for the Kv1.3 channel over a range of other ion channels, including Na+, K+, and Ca2+. It also showed unique DMPK profiles, high colon/ileum concentrations with low systemic exposure in multiple species, demonstrating an excellent safety profile in preclinical studies.'Although antibodies play a pivotal role in the treatment of moderate to severe IBD, their applications are limited by constrained therapeutic efficacy, immunogenicity, parenteral route of drug delivery, poor tolerability, and high cost.' said Xiaomin Zhang, Head of Drug Discovery at DP Technology. 'As a small molecule, DPT0218 has shown potent inhibition of T cell activation, proliferation, and cytokine secretion in both in vivo and in vitro studies, demonstrating its potential as an effective treatment for IBD.

它在各种自身免疫性疾病（如IBD和AD）的临床前动物模型中显示出积极的结果。该化合物具有亚纳摩尔效力，并且对Kv1.3通道的选择性比其他一系列离子通道（包括Na+，K+）高2000倍。和Ca2+。它还显示出独特的DMPK谱，结肠/回肠浓度高，多个物种的全身暴露低，在临床前研究中表现出优异的安全性。”尽管抗体在治疗中重度IBD中起着关键作用，但其应用受到治疗效果，免疫原性，肠胃外给药途径，耐受性差和成本高的限制。”DP Technology药物研发负责人张晓敏表示。作为一种小分子，DPT0218在体内和体外研究中均显示出对T细胞活化，增殖和细胞因子分泌的有效抑制，证明了其作为IBD有效治疗的潜力。

We'll actively advance DPT0218 to clinical research and explore its application to other autoimmune diseases.''DP Technology is the pioneer of AI for Science paradigm, dedicated to integrating 'AI + Simulation + Experiments' to address unmet clinical needs.' said Weijie Sun, Founder and CEO of DP Technology. 'The dynamics of ion channels are extremely complicated, and our RiDYMO® platform is unequivocally well-suited for.

我们将积极推进DPT0218的临床研究，并探索其在其他自身免疫性疾病中的应用DP技术是人工智能科学范式的先驱，致力于整合“人工智能+模拟+实验”以解决未满足的临床需求DP Technology创始人兼首席执行官孙伟杰表示。“离子通道的动力学非常复杂，我们的RiDYMO®平台无疑非常适合。

[1] Chiang EY, Li T, Jeet S, et al. Potassium channels Kv1.3 and KCa3.1 co-operatively and compensatorily regulate antigen-specific memory T cell functions. Nat Commun 2017:14644.

[1] Chiang EY，Li T，Jeet S等。钾通道Kv1.3和KCa3.1协同并补偿调节抗原特异性记忆T细胞功能。Nat Commun 2017:14644。

[2] Lin CS, Boltz RC, Blake JT, et al. Voltage-gated potassium channels regulate calcium-dependent pathways involved in human T lymphocyte activation. J Exp Med 1993:637–45.

[2] Lin CS，Boltz RC，Blake JT等。电压门控钾通道调节参与人T淋巴细胞活化的钙依赖性途径。J Exp Med 1993:637-45。

[3] Sandborn WJ, Su C, Sands BE, et al.; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain Investigators. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2017:1723–36.

[3] Sandborn WJ，Su C，Sands BE等。；倍频程诱导1，倍频程诱导2和倍频程维持研究者。托法替尼作为溃疡性结肠炎的诱导和维持治疗。英格兰医学杂志2017:1723-36。

[4] John T. Chang. Pathophysiology of Inflammatory Bowel Diseases. N Engl J Med 2020:2652-64.

[4] 约翰·T·张。炎症性肠病的病理生理学。英国医学杂志2020:2652-64。

[5] Anna-Lena Unterweger, Morten Ø. Jensen, Fabrizio Giordanetto, et al. Suppressing Kv1.3 Ion Channel Activity with a Novel Small Molecule Inhibitor Ameliorates Inflammation in a Humanised Mouse Model of Ulcerative Colitis. Journal of Crohn's and Colitis 2021:1943–58.

[5] Anna Lena Unterweger，莫滕Ø。Jensen，Fabrizio Giordanetto等人。用新型小分子抑制剂抑制Kv1.3离子通道活性可改善溃疡性结肠炎人源化小鼠模型的炎症。克罗恩病和结肠炎杂志2021:1943-58。

SOURCE DP Technology

源DP技术