7 research outputs found
Iberdomide (CC-220) Has Synergistic Anti-Tumor and Immunostimulatory Activity Against Multiple Myeloma in Combination with Both Bortezomib and Dexamethasone, or in Combination with Daratumumab in Vitro
P997: FEDRATINIB IS EFFECTIVE IN RUXOLITINIB-RESISTANT CELLS: CLINICAL AND PRECLINICAL CORRELATIONS
Loss Of COP9-Signalosome Genes At 2q37 Is Associated With IMiD Agent Resistance In Multiple Myeloma
The acquisition of a multi-drug refractory state is a major cause of mortality in myeloma. Myeloma drugs that target the Cereblon (CRBN) protein include widely-used immunomodulatory drugs (IMiDs), and newer CRBN E3 ligase modulator drugs (CELMoDs), in clinical trials. CRBN genetic disruption causes resistance and poor outcomes with IMiDs. Here we investigate alternative genomic associations of IMiD resistance, using large whole genome sequencing patient datasets (n=522 cases) at newly diagnosed, lenalidomide (LEN)-refractory and lenalidomide-then-pomalidomide (LEN-then-POM)-refractory timepoints. Selecting gene targets reproducibly identified by published CRISPR/shRNA IMiD resistance screens, we found little evidence of genetic disruption by mutation associated with IMiD resistance. However, we identified a chromosome region, 2q37, containing COP9-signalosome members COPS7b and COPS8, copy loss of which significantly enriches between newly-diagnosed (incidence 5.5%), LEN-refractory (10.0%) and LEN-then-POM-refractory states (16.4%), and may adversely affect outcomes when clonal fraction is high. In a separate dataset (50 patients) with sequential samples taken throughout treatment, we identified acquisition of 2q37 loss in 16% cases with IMiD exposure, but none in cases without IMiD exposure. The COP9 signalosome is essential for maintenance of the CUL4-DDB1-CRBN E3 Ubiquitin Ligase. This region may represent a novel marker of IMiD resistance with clinical utility
Benzazepinones and Benzoxazepinones as Antagonists of Inhibitor of Apoptosis Proteins (IAPs) Selective for the Second Baculovirus IAP Repeat (BIR2) Domain
XIAP is a key regulator of apoptosis,
and its overexpression in
cancer cells may contribute to their survival. The antiapoptotic function
of XIAP derives from its BIR domains, which bind to and inhibit pro-apoptotic
caspases. Most known IAP inhibitors are selective for the BIR3 domain
and bind to cIAP1 and cIAP2 as well as XIAP. Pathways activated upon
cIAP binding contribute to the function of these compounds. Inhibitors
selective for XIAP should exert pro-apoptotic effects through competition
with the terminal caspases. This paper details our synthetic explorations
of a novel XIAP BIR2-selective benzazepinone screening hit with a
focus on increasing BIR2 potency and overcoming high in vivo clearance.
These efforts led to the discovery of benzoxazepinone <b>40</b>, a potent BIR2-selective inhibitor with good in vivo pharmacokinetic
properties which potentiates apoptotic signaling in a manner mechanistically
distinct from that of known pan-IAP inhibitors
Optimization of Benzodiazepinones as Selective Inhibitors of the X‑Linked Inhibitor of Apoptosis Protein (XIAP) Second Baculovirus IAP Repeat (BIR2) Domain
The
IAPs are key regulators of the apoptotic pathways and are commonly
overexpressed in many cancer cells. IAPs contain one to three BIR
domains that are crucial for their inhibitory function. The pro-survival
properties of XIAP come from binding of the BIR domains to the pro-apoptotic
caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while
the BIR2 domain binds and inhibits the terminal caspases 3 and 7.
While XIAP BIR3 inhibitors have previously been reported, they also
inhibit cIAP1/2 and promote the release of TNFα, potentially
limiting their therapeutic utility. This paper will focus on the optimization
of selective XIAP BIR2 inhibitors leading to the discovery of highly
potent benzodiazepinone <b>36</b> (IC<sub>50</sub> = 45 nM),
which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3
and shows efficacy in a xenograft pharmacodynamic model monitoring
caspase activity while not promoting the release of TNFα in
vitro