Bruton’s Tyrosine Kinase (BTK) is an established target in drug discovery. Due to its role in B-cell proliferation and activation, inhibition has shown clinical benefit in B-cell driven lymphomas as well as autoimmune diseases including Multiple Sclerosis (MS). One hypothesis for the pathogenesis of MS is B-cells infiltrate into the CNS, where they contribute to disease progression through CNS resident inflammation. Since BTK controls B-cell differentiation and activation, inhibition of BTK could halt disease progression. It has been challenging to achieve the desired target coverage in the CNS safely with reversible BTK inhibitors. CNS penetrant covalent BTK inhibitors have emerged and have demonstrated MS clinical efficacy, but concerns around safety due to chronic treatment of a covalent inhibitor remain. A degrader offers the advantage of prolonged pharmacology due to the long BTK resynthesis rate through a non-covalent mechanism which may result in improved safety. In this poster, we will disclose the design, synthesis, in vitro, and in vivo characterization of orally available CNS penetrant BTK degraders. We will also compare the efficacy of our degrader to a clinical covalent inhibitor in a mouse anti-MOG model of BTK driven microglia proliferation.