Discovery of a Novel Benzodiazepine Series of Cbl-b Inhibitors for the Enhancement of Antitumor Immunity

Boerth, Jeffrey A.; Chinn, Alex J.; Schimpl, Marianne; Bommakanti, Gayathri; Chan, Christina; Code, Erin L.; Giblin, Kathryn A.; Gohlke, Andrea; Hansel, Catherine S.; Jin, Meizhong; Kavanagh, Stefan L.; Lamb, Michelle L.; Lane, Jordan S.; Larner, Carrie J. B.; Mfuh, Adelphe M.; Moore, Rachel K.; Puri, Taranee; Quinn, Taylor R.; Ye, Minwei; Robbins, Kevin J.; Gancedo-Rodrigo, Miguel; Tang, Haoran; Walsh, Jarrod; Ware, Jamie; Wrigley, Gail L.; Reddy, Iswarya Karapa; Zhang, Yun; Grimster, Neil P.

doi:10.1021/acsmedchemlett.3c00439

Cited by 4 publications

(3 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, our SH2 domain binders (shown in red) displayed a similar potency in both assays. This was an unexpected finding in light of the reports of drastic conformational change of Cbl-b between the active and inactive state and suggests to us that the SH2 domain binders interact with Cbl-b enzyme with similar affinity regardless of its state. , …”

Section: Results and Discussionmentioning

confidence: 70%

“…This was an unexpected finding in light of the reports of drastic conformational change of Cbl-b between the active and inactive state and suggests to us that the SH2 domain binders interact with Cbl-b enzyme with similar affinity regardless of its state. 27,28 As mentioned above, we were interested in exploring if Cblb selectivity is achievable over c-Cbl and, if so, whether there is any advantage for selective inhibition of Cbl-b versus Cbl-b and c-Cbl. As a result, we prepared an active c-Cbl enzyme and developed the corresponding ZAP70 assay.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…However, 2 was found to be inactive when tested with cells, likely due to poor cell permeability because of its high polarity. Guided by cocrystal structure and properties, we systematically evaluated and optimized the different substructure of 2 to arrive at an optimized compound (27), which showed cellular activity at high concentrations. Additionally, we demonstrated that our SH2 domain binders had similar potencies for both activated (ZAP70 assay) and inactive (Lck assay) Cbl-b, thereby suggesting that the SH2 domain binders can effectively inhibit…”

Section: ■ Results and Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Optimization of a Novel DEL Hit That Binds in the Cbl-b SH2 Domain and Blocks Substrate Binding

Liang,

Lambrecht,

Arenzana

et al. 2024

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

We were attracted to the therapeutic potential of inhibiting Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), a RING E3 ligase that plays a critical role in regulating the activation of T cells. However, given that only protein–protein interactions were involved, it was unclear whether inhibition by a small molecule would be a viable approach. After screening an ∼6 billion member DNA-encoded library (DEL) using activated Cbl-b, we identified compound 1 as a hit for which the cis-isomer (2) was confirmed by biochemical and surface plasmon resonance (SPR) assays. Our hit optimization effort was greatly accelerated when we obtained a cocrystal structure of 2 with Cbl-b, which demonstrated induced binding at the substrate binding site, namely, the Src homology-2 (SH2) domain. This was quite noteworthy given that there are few reports of small molecule inhibitors that bind to SH2 domains and block protein–protein interactions. Structure- and property-guided optimization led to compound 27, which demonstrated measurable cell activity, albeit only at high concentrations.

show abstract

Section: Results and Discussionmentioning

confidence: 70%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

See 1 more Smart Citation