尊龙Z6官方网站

尊龙Z6官方网站医药（港交所代码：02256）在2023年美国癌症钻研协会（AACR）年会上颁布了五项最新临床前钻研了局。

其中蕴含其自主研发的已获中美双突破性疗法认定的CSF-1R抑造剂Pimicotinib（ABSK021）和可能成为best-in-class 的新一代克服耐药突变的EGFR Exon20抑造剂ABSK112，以及新一代克服耐药突变的FGFR4 抑造剂ABSK012和FGFR抑造剂ABSK121，新一代KRAS抑造剂ABSK071的最新临床前和转化医学钻研进展。

尊龙Z6官方网站医药在本届AACR年会上展示了以下壁报：

标题: 

A potent and selective small molecule inhibitor of CSF-1R ABSK021 demonstrates strong efficacy in preclinical models of osteosarcoma

CSF-1R强效选择性幼分子抑造剂ABSK021在临床前骨赘瘤模型中显示出壮大的药效

提要编号: LB329

钻研布景：

Osteosarcoma is the most common primary malignant bone tumor in children and young adults. Surgery combined with multimodal chemotherapy remains as the standard treatment for osteosarcoma patients. However, patients with osteosarcoma metastasis have a five-year survival rate of less than 30%, and their long-term outcomes have not improved over the last 30 years, representing a high unmet medical need. CSF-1/CSF-1R signaling is crucial for the survival, function, proliferation and differentiation of myeloid lineage cells, including osteoclasts and monocytes/macrophages. Targeting CSF-1R either on tumor cells or tumor-associated macrophages has been reported to limit osteosarcoma progression in preclinical models. ABSK021, an oral, highly potent and selective small molecule inhibitor of CSF-1R, showed significant anti-tumor activity and favorable safety profile in patients with advanced tenosynovial giant cell tumor in phase 1b trial. We demonstrated the treatment potential of ABSK021 for osteosarcoma patients through a series of preclinical in vitro and in vivo experiments, as well as human osteosarcoma profiling.

骨赘瘤是儿童和年轻人中最常见的原发性恶性骨肿瘤。目前手术结合多种化疗是骨赘瘤患者的尺度医治步骤。然而，骨赘瘤转移患者的五年生计率不到 30%，在从前 30 年中持久预后也未得到改善，这是一个高度未被满足的医疗需要。CSF-1/CSF-1R信号通路对于髓系细胞，蕴含破骨细胞和单核/巨噬细胞的存活、职能、增殖和分化至关沉要。据报路，在临床前模型中，靶向肿瘤细胞或者肿瘤有关巨噬细胞上的CSF-1R能够限度骨赘瘤的进展。ABSK021是一个口服，高活性和高选择性的CSF-1R幼分子抑造剂，在临床1b试验中对晚期腱鞘大幼胞瘤患者展示出显著的抗肿瘤疗效和优良的安全性。通过一系列临床前体表和体内尝试，以及骨赘瘤患者的表白分析，我们证了然ABSK021拥有医治骨赘瘤患者的潜力。

结论：

ABSK021 has strong inhibition of CSF-1R activity and corresponding anti-tumor activity in preclinical osteosarcoma models. High prevalence of CSF-1R expression was also found in osteosarcoma patients, suggesting great potential of utilizing ABSK021 as a novel therapy to treat osteosarcoma patients in clinic.

ABSK021在临床前骨赘瘤模型中展示出强效的CSF1R活性抑造和相应的抗肿瘤活性。在骨赘瘤患者中也发现了高比例的CSF1R表白，批注ABSK021拥有在临床上成为骨赘瘤新的医治步骤的巨大潜力。

标题: 

ABSK112, a potential best-in-class EGFR exon 20 mutant Inhibitor with excellent selectivity and brain penetration

潜在最优EGFR exon20突变的幼分子抑造剂ABSK112, 拥有极佳选择性和入脑个性

提要编号: LB327

钻研布景：

EGFR Exon20 mutations are clinically validated oncogenic alterations including a wide spectrum of mutations occurring in lung cancer and various other cancer types. Although several EGFR Exon20 inhibitors have reached clinical stage or received approval, there still leave large room for improvement in safety and efficacy, likely due to their limited selectivity against wild-type EGFR or other kinases, suboptimal mutation coverage, and lack brain penetrating ability. Herein, we have discovered a novel and next-generation EGFR Exon20 mutation inhibitor, ABSK112. It showed high selectivity over wild-type EGFR and other kinases, as well as a more comprehensive coverage over majority of EGFR Exon20 mutations in comparison with other EGFR Exon20 inhibitors.

EGFR表显子20插入突变蕴含了一系列突变，是临床上确证的致癌性突变，在肺癌和其他多种肿瘤中均有产生。只管已经有一些EGFR 表显子20插入突变抑造剂进入临床阶段或获得的临床批件，但由于诸如针对野生型EGFR或其他激酶的选择性有限，突变覆盖不齐全，以及不足入脑个性等问题，在安全性和有效性上还留有很猛进取空间；诖，我们开发了全新的下一代EGFR表显子20插入突变抑造剂ABSK112。与其他同类抑造剂相比，它阐发出针对野生型EGFR和其他激酶的优良选择性，同时可能覆盖绝大部门 EGFR表显子20插入突变谱，并且有很好的入脑个性。

结论：

ABSK112 is a leading next-generation EGFR Exon20ins inhibitor with improved selectivity over wild-type EGFR and strong brain penetrating ability. It shows superior in vivo efficacy in various EGFR Exon20ins xenograft models, and broader spectrum of mutation coverage than clinical stage competitors.

ABSK112是当先的新一代EGFR表显子20插入突变抑造剂，拥有针对比野生型EGFR的高选择性和高脑穿透能力，并且在各类EGFR表显子20插入突变的异种移植模型中拥有杰出的体内功效，比临床阶段竞争敌手拥有更宽泛的突变覆盖领域。

标题: 

Discovery & characterization of a next-generation FGFR4 inhibitor overcoming resistant mutations

能够克服耐药突变的新一代FGFR4抑造剂的发现和表征

提要编号: LB328

钻研布景：

Aberrant activation of FGF19-FGFR4 signaling pathway plays an essential role in the tumorigenesis of Hepatocellular carcinoma (HCC) and FGFR4 inhibitors have shown preliminary efficacy in recent clinical trials for patients with FGF19 overexpression. However, the observed responses only lasted a few months before tumors relapse. Acquired FGFR4 resistant mutations were found in ~30% of FGFR4 inhibitor responsive patients. Similar FGFR4 mutations haven also been found de novo in about 7-10% of Rhabdomyosarcoma (RMS) and ER-treated invasive lobular carcinoma patients. First generation FGFR4 inhibitors have minimal activity against these de novo or acquired resistant mutations. Therefore, next-generation of FGFR4 inhibitors are needed to overcome these resistant FGFR4 mutations to provide better treatment options for patients. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a next-generation small molecule FGFR4 inhibitor, ABSK012, and demonstrated its strong activities against de novo and acquired resistant FGFR4 mutations while retaining inhibition for wild-type FGFR4.  

成纤维细胞成长因子(FGF)19和成纤维细胞成长因子受体（FGFR）4信号通路的过度激活在肝细胞癌（HCC）的癌症产生过程中表演着极度沉要的角色，FGFR4抑造剂也已经在临床尝试中显示出对于FGF19过表白病人的药效。然而，所观察到的临床活性时时在几个月后就产生了肿瘤的复发。在约莫30%的FGFR4抑造剂有效的病人中城市有获得性的FGFR4耐药突变的产生。类似的FGFR4突变也被发此刻7-10%的横纹肌赘瘤（RMS）以及雌激素受体阳性的侵入性的幼叶乳腺癌病人中。一代的FGFR4抑造剂对于这些获得性或者新生的耐药突变险些没有活性。因而，必要新一代的FGFR4抑造剂为病人提供更好的医疗规划。选取推算机辅助结构设计以及药物化学的设计，我们发现了一个新一代的FGFR4抑造剂，ABSK012.它在新生及获得性的FGFR4耐药突变中展示了很强的活性，且对野生型的FGFR4也保留了很强的抑造。

结论：

ABSK012, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR4 inhibitor overcoming FGFR4 mutations resistant to first-generation inhibitors. Its superior preclinical profile supports its fast-track development into clinic.

这些数据初次证了然ABSK012是新一代的高选择性的强效幼分子 FGFR4 抑造剂，并且能够克服FGFR4的耐药突变。它优良的临床前性质支持它尽快进入临床开发阶段进行评估。

标题: 

Discovery and characterization of a next-generation FGFR inhibitor overcoming FGFR resistant mutations

能够克服耐药突变的新一代FGFR抑造剂的发现和表征

提要编号: LB317

钻研布景：

FGFRs play important roles in cancer development and inhibition of FGFR could disrupt tumor cell proliferation and growth. Four selective FGFR inhibitors have been approved (erdafitinib, pemigatinib, infigratinib, and futibatinib) and several others are in clinical development. Unfortunately upon treatment with these first-generation FGFR inhibitors, acquired resistance often develops and is frequently associated with the emergence of secondary FGFR2/3 kinase domain mutations. Therefore, selectively targeting FGFR2/3 as well as their resistant mutations may render a second-generation treatment approach for the refractory/relapsed patients. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a novel, next-generation, and highly selective FGFR inhibitor, ABSK121. This novel inhibitor demonstrated robust anti-tumor activity in FGFR-dependent tumor models with strong activities against not only de novo but also acquired resistant mutations.

成纤维细胞成长因子受体(FGFR)在肿瘤的发展中有沉要的作用，抑造FGFR能够故障肿瘤细胞的增殖和成长。有四个选择性的FGFR抑造剂被核准上市（erdafitinib, pemigatinib, infigratinib, 以及 futibatinib），还有一些其他在临床开发阶段。不幸的是，在这些一代的FGFR抑造剂医治之后，经；岵竦眯缘哪鸵，并且时时和次生的FGFR2/3激酶区域突变的产生有关。因而选择性的靶向FGFR2/3以及它们的耐药突变，可以为复发的病人提供二代的医治伎俩。选取推算机辅助结构设计以及药物化学的设计，我们发现了一个新的下一代的选择性FGFR抑造剂，ABSK121。它在FGFR依赖性的肿瘤模型中展示了极度好的抗肿瘤活性，并且对新生及获得性的FGFR耐药突变都有很强的活性。在本次壁报中，我们展示了ABSK121的临床前体表和体内数据。

结论：

ABSK121, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR inhibitor with great potency against resistant FGFR mutations. Its superior profile supports fast-track preclinical and clinical development.

这些数据初次证了然ABSK121是新一代的高选择性的强效幼分子 FGFR抑造剂，并且能够克服FGFR的耐药突变。它优良的临床前性质支持它尽快进入临床开发阶段进行评估。

标题: 

A next-generation KRASG12C inhibitor ABSK071 demonstrated broad synergy with other therapeutic agents in KRASG12C mutated cancer models

新一代KRAS G12C抑造剂ABSK071在KRAS G12C突变肿瘤模型中与其他药物联用阐发出宽泛的结合用药成效提要编号: LB316

钻研布景：

KRAS is frequently mutated in human cancers, including pancreatic (~90%), colorectal (~35%), and lung cancer (~25%). The KRASG12C mutation (single amino acid substitution of cysteine for glycine at position 12) accounts for ~14% of lung cancer, ~4% of colorectal cancer, and ~2% of pancreatic cancer. Currently, two covalent KRASG12C inhibitors, namely sotorasib (AMG-510) and adagrasib (MRTX-849), have been approved as monotherapy to treat locally advanced or metastatic NSCLC with KRASG12C mutation through accelerated approval process.

Despite the beneficial effects of KRASG12C inhibitors in clinic for certain patients, the limited antitumor efficacy in most patients and potential drug resistance are major concerns. A next-generation inhibitor with better inhibitory activity may improve anti-tumor efficacy. Combination with other therapeutic agents may also improve the single-agent activity of KRASG12C inhibitors. These approaches could both overcome the limitations of sotorasib and adagrasib and provide additional benefits to patients.

KRAS基因在人类肿瘤中时时产生突变，在约90%的胰腺癌、约35%的结直肠癌和约25%肺癌病人中会产生KRAS基因的突变。KRAS G12C突变(第12位的甘氨酸突变为半胱氨酸)约占肺癌的14%，结直肠癌的4%，以及胰腺癌的2%。目前，已有两种KRAS G12C共价抑造剂通过FDA的加快审批法式被核准上市，单药用以医治伴有KRAS G12C突变的部门晚期或转移性非幼细胞肺癌（NSCLC），它们别离为安进公司的Sotorasib (AMG-510)和Mirati公司的Adagrasib (MRTX-849)。

只管使用KRAS G12C抑造剂的部门患者阐发出肯定的临床获益，但对大无数患者来说其抗肿瘤成效有限，并且存在潜在的耐药风险。因而，一方面必要开发抗肿瘤活性更好的新一代KRAS G12C抑造剂以提高抗肿瘤成效，另一方面必要通过与其他药物的结合用药来提高KRAS G12C抑造剂的抗肿瘤活性。这些步骤能够克服Sotorasib和Adagrasib的局限性，并为患者带来更大的临床获益。

结论：

ABSK071 is a next-generation KRASG12C inhibitor with greater activity and anti-tumor efficacy in vitro and in vivo. It also demonstrated broad synergistic effects with a large set of targeted agents and immuno-oncology agents, indicating its strong potential in combinatory therapy in treating a wider range of KRASG12C-dependent cancers.

ABSK071是新一代KRAS G12C抑造剂，阐发出更强的体表生物学活性以及体内抗肿瘤药效。ABSK071与多种靶向医治药物和免疫医治药物联用阐发出宽泛的结合用药成效，预示着其拥有更大的结合用药潜力用以医治更多的KRAS G12C突变的肿瘤患者。