近日，Cullgen公开专利一项TYK2-PROTAC降解剂的专利《Tyrosine kinase 2 (TYK2) degradation compounds and methods of use》，该专利申请于2020年11月，TYK2靶蛋白配体连接VHL和CRBN配体。该靶点已由BMS验证在PsO适应症的疗效，并于2021年11月向FDA提交上市申请，除此适应症外，BMS的Deucravacitinib还在PsA（Ph3）、SLE（Ph2） 以及UC（Ph2 failed）等领域拓展。
以下是部分实施例结构以及在MOLT-4, NOMO-1 or Jurkat cells降解活性，那么Cullgen会在什么适应症尝试呢？
| Cullgen实施例内容 |
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The preferred benefit to risk ratio of targeting TYK2 has increasingly attracted the interests of academia and pharmaceutical industry. Neutralizing antibodies against IL-12 and IL-23, the main cytokines that signal through TYK2, have been approved for treating psoriasis, psoriatic arthritis and Crohn’s disease. Over the past decade, a variety of TYK2 kinase inhibitors with varying degree of selectivity over other JAK family members have been reported and patented. Some of these TYK2 inhibitors have proceeded into different clinical stages.
While TYK2 and other JAK kinase inhibitors hold promises treating a wide range of immunologic and malignant condition, small molecule inhibitors primarily modulate the catalytic activities of these kinases. However, TYK2 can contribute to cytokine signaling through its scaffolding functions. Kinase-dead TYK2 mutants retain the ability to regulate stability of receptors of type I interferon. The catalytic functions of TYK2 are also dispensable for activation of PI3K signaling. Therefore, depletion of TYK2 using small molecule degraders may have more profound impact on cytokine response than kinase inhibitors.
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