Spleen tyrosine kinase (SYK) and Janus kinase (JAK) play important roles in the pathogenesis of various types of lymphomas, solid tumors, myeloproliferative and inflammation disorders. Inhibition of these targets has been shown to suppress tumor growth in various preclinical and/or clinical studies. Most B-cell malignancies are driven by the B-cell receptor (BCR) pathway, and SYK plays a critical role in this pathway by initiating and amplifying the signal from the receptor. JAK kinases (JAK1, JAK2, JAK3 and TYK2), upon stimulation by various growth factors and cytokines, phosphorylate signal transducers and activators of transcription family proteins (STAT1 -5) which activate various downstream target genes. ASN002 is a novel and potent dual inhibitor of SYK and JAK kinases with IC50 values of 5-46 nM in biochemical assays. In mechanistic cell-based studies involving IgE and cytokine stimulations, ASN002 strongly suppressed the SYK and JAK family kinase signaling pathways measured as pLAT and pSTAT levels, respectively. The compound showed anti-proliferative activity in a broad panel of human cancer cell lines including DHL6, DHL4, OCI-LY10, H929, Pfeiffer, HT-1376, and Lovo, suggesting activity in both solid and hematological tumor types. In a multiple myeloma (H929) xenograft model, ASN002 exhibited significant efficacy in inhibiting tumor growth (>95%). It also significantly delayed the onset of hind limb paralysis in the human erythroleukemia (HEL) mouse model. ASN002 has good oral bioavailability, metabolic stability, is not a Pgp substrate, and shows little to no inhibition of CYP450 isozymes. ASN002 showed a favorable safety profile in rat and dog toxicology studies. A Phase I/II clinical study is being planned for the evaluation of ASN002 in lymphomas (diffuse large B cell lymphoma, mantle cell lymphoma, follicular lymphoma) and solid tumors.

Citation Format: Sanjeeva Reddy, Nitin K. Damle, Aranapakam M. Venkatesan, Scott K. Thompson, Niranajan Rao, Roger A. Smith, Sandeep Gupta. ASN002: A novel dual SYK/JAK inhibitor with strong antitumor activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 792. doi:10.1158/1538-7445.AM2015-792