Lenalidomide achieves its therapeutic efficacy by recruiting and removing proteins of therapeutic interest through the E3 ligase substrate adapter cereblon. Here, we report the design and characterization of 81 cereblon ligands for their ability to degrade the transcription factor Helios (IKZF2) and casein kinase 1 alpha (CK1α). We identified a key naphthamide scaffold that depleted both intended targets in acute myeloid leukemia MOLM-13 cells. Structure-activity relationship studies for degradation of the desired targets over other targets (IKZF1, GSPT1) afforded an initial lead compound DEG-35. A subsequent scaffold replacement campaign identified DEG-77, which selectively degrades IKZF2 and CK1α, and possesses suitable pharmacokinetic properties, solubility, and selectivity for in vivo studies. Finally, we show that DEG-77 has antiproliferative activity in the diffuse large B cell lymphoma cell line OCI-LY3 and the ovarian cancer cell line A2780 indicating that the dual degrader strategy may have efficacy against additional types of cancer.

01 Apr 2023·Cancer Cell

Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells

Article

Author: Schurer, Alexandra ; Chang, Kathryn ; Kharas, Michael G ; Park, Sun-Mi ; Curnutt, Nicole M ; Miyamoto, David K ; Xu, Wenqing ; Woo, Christina M ; Han, Grace Y Q ; Tran, Nathan L ; Kim, Jun Hyun ; Velleca, Anthony ; Chan, Mandy

Acute myeloid leukemia (AML) is a hematologic malignancy for which several epigenetic regulators have been identified as therapeutic targets. Here we report the development of cereblon-dependent degraders of IKZF2 and casein kinase 1α (CK1α), termed DEG-35 and DEG-77. We utilized a structure-guided approach to develop DEG-35 as a nanomolar degrader of IKZF2, a hematopoietic-specific transcription factor that contributes to myeloid leukemogenesis. DEG-35 possesses additional substrate specificity for the therapeutically relevant target CK1α, which was identified through unbiased proteomics and a PRISM screen assay. Degradation of IKZF2 and CK1α blocks cell growth and induces myeloid differentiation in AML cells through CK1α-p53- and IKZF2-dependent pathways. Target degradation by DEG-35 or a more soluble analog, DEG-77, delays leukemia progression in murine and human AML mouse models. Overall, we provide a strategy for multitargeted degradation of IKZF2 and CK1α to enhance efficacy against AML that may be expanded to additional targets and indications.

01 Nov 2015·Nature GeneticsQ1 · BIOLOGY

Integrated molecular analysis of adult T cell leukemia/lymphoma

Q1 · BIOLOGY

Article

Author: Yoon, Sung-Soo ; Shiraishi, Yuichi ; Totoki, Yasushi ; Makishima, Hideki ; Ishiyama, Ken ; Nureki, Osamu ; Kubuki, Yoko ; Shide, Kotaro ; Sanada, Masashi ; Sasai, Ken ; Tobinai, Kensei ; Munakata, Wataru ; Penova, Marina ; Tanaka, Hiroko ; Sato, Yusuke ; Iwanaga, Masako ; Kotani, Shinichi ; Nagae, Genta ; Nakamura, Hiromi ; Matsuoka, Masao ; Itonaga, Hidehiro ; Matsuda, Fumihiko ; Nakamaki, Tsuyoshi ; Takeuchi, Kengo ; Hama, Natsuko ; Watanabe, Toshiki ; Shimamura, Teppei ; Yoshida, Kenichi ; Watatani, Yosaku ; Muto, Satsuki ; Hishizawa, Masakatsu ; Miyawaki, Shuichi ; Imaizumi, Yoshitaka ; Miyazaki, Yasushi ; Aburatani, Hiroyuki ; Yoshizato, Tetsuichi ; Kameda, Takuro ; Sato-Otsubo, Aiko ; Nagata, Yasunobu ; Miyano, Satoru ; Kataoka, Keisuke ; Nosaka, Kisato ; Yasunaga, Jun-Ichirou ; Kawaguchi, Takahisa ; Hidaka, Tomonori ; Takaori-Kondo, Akifumi ; Takeda, June ; Ma, Guangyong ; Suzuki, Hiromichi ; Ogawa, Seishi ; Chiba, Kenichi ; Muramoto, Kenzo ; Sato, Toshitaka ; Ishii, Ryohei ; Shimoda, Kazuya ; Kitanaka, Akira ; Shiozawa, Yusuke ; Ogasawara, Hideaki ; Shibata, Tatsuhiro

Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-κB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.

Analysis

Perform a panoramic analysis of this field.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis