On March 29, 2019 Kymera Therapeutics Inc., a biotechnology company pioneering targeted protein degradation to create breakthrough medicines for patients, reported that it will present new preclinical data for its first-in-class oral IRAK4 protein degrader, KYM-001, in MYD88-mutant lymphoma (Press release, Kymera Therapeutics, MAR 29, 2019, View Source [SID1234534793]). Data will be presented in a late-breaking research session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting on April 3 from 8 a.m. – 12 p.m. (Poster #18, Session: Experimental and Molecular Therapeutics 2). The study showed that KYM-001 led to highly selective degradation of IRAK4 and tumor regression upon oral dosing, both alone and in combination with BTK inhibition.

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"IRAK4 degraders offer an entirely new therapeutic approach to treat MYD88-driven B cell lymphomas, which are often aggressive and have a poor prognosis," said Nello Mainolfi, PhD, co-founder and Chief Scientific Officer, Kymera Therapeutics and study co-author. "IRAK4 kinase and scaffolding functions are critical to MYD88-driven Myddosome signaling. Unlike conventional kinase inhibitors, our novel degrader KYM-001 removes both the kinase and scaffolding function of IRAK4 to effectively block Myddosome signaling, resulting in tumor growth arrest and subsequent regression. The team has been able to very quickly identify orally active degraders that offer ease and flexibility of dosing. "

MYD88-activating mutations occur in 30-40% of patients with activated B cell-like (ABC) diffuse large B cell lymphoma (DLBCL). This study assessed the antitumor activity of Kymera’s orally active small molecule degraders in human ABC DLCBL cell lines in vitro and in tumor xenograft models in vivo, alone and in combination with the BTK inhibitor ibrutinib.

Study Highlights "KYM-001, a first-in-class oral IRAK4 protein degrader, induces tumor regression in xenograft models of MYD88-mutant ABC DLBCL alone and in combination with BTK inhibition":

KYM-001 induced potent and selective E3 ligase-dependent degradation of IRAK4 in multiple cellular models, resulting in 90% degradation at concentrations less than 100 nM.
KYM-001 induced comparable levels of IRAK4 degradation in both MYD88 mutant and MYD88 WT human ABC DLBCL cell lines.
KYM-001 impacted viability in MYD88 mutant, but not WT, ABC DLBCL cell lines, inducing apoptotic effects within 72 hours.
Oral dosing of KYM-001 showed dose-dependent antitumor activity against the MYD88 L265P mutant ABC DLBCL cell line OCI-LY10, with >80% degradation of IRAK4 correlating with tumor regression in xenograft-bearing mice.
KYM-001 was synergistic with the BTK inhibitor ibrutinib in vitro in ABC DLBCL cell lines bearing both MYD88 L265P and CD79 mutations. In vivo, this combined activity resulted in tumor regression at concentrations that were sub-optimal in single-agent studies, supporting further exploration of combinations that target oncogenic NFκB signaling.