Andrew F. Donnell

B-lymphocyte-induced maturation protein 1 (BLIMP-1/PRDM1) is a master transcriptional repressor essential for terminal differentiation of activated B-cells into bone-marrow resident plasma cells. Multiple myeloma (MM) is a plasma cell malignancy wherein the BLIMP-1 regulon remains critical to support basal cell functions, such as an elevated metabolic state and immunoglobulin production that underlie disease manifestation and tumor cell proliferation. It is predicted that perturbation of BLIMP-1 will significantly impact tumor cell homeostasis and ultimately reduce MM cell survival. Herein, we describe the discovery and optimization of the first orally bioavailable BLIMP-1 heterobifunctional ligand-directed degrader (LDD) and demonstration of the expected antitumor response and immunomodulatory biology following BLIMP-1 degradation using preclinical in vivo MM models.

Ubiquitin-like modifier activating enzyme 5 (UBA5), an E1 enzyme in the UFMylation pathway, is of interest as a therapeutic target in diseases such as cancer due to the critical role that UFMylation plays in cellular function. Strategic structure–activity relationship optimization of high-throughput screen hit 6, a Bruton’s tyrosine kinase covalent inhibitor, was conducted by using both conventional and microscale library synthesis. This approach identified 49 and 50 as potent and selective noncovalent UBA5 inhibitors with significantly improved surface plasmon resonance and nanodifferential scanning fluorimetry biophysical profiles. Cellular target engagement for 49 and 50 was confirmed by a cellular thermal shift assay and translated to inhibition of UFMylation of UBA5 and UFC1 in retinal pigment epithelial-1 cells as well as reduction of UFMylation of the downstream protein UFMylation substrate RPL26. Furthermore, 49 and 50 demonstrated specificity for UBA5 among the other E1–E2 transesterification pathways. In this communication, we report the discovery and synthesis of potent and selective UBA5 inhibitors, providing valuable tool compounds for studying the UFMylation pathway.

Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure-activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound 14, which displayed nanomolar reporter assay activity and favorable drug-like properties. Compound 14 demonstrated excellent in vivo pharmacokinetic/pharmacodynamic profiles and synergistic antitumor activity when administered in combination with aPD1 antibody, suggesting opportunities of employing 14 in immuno-oncology therapies with immune checkpoint blockade agents.

We have designed and developed novel and selective TLR7 agonists that exhibited potent receptor activity in a cell-based reporter assay. In vitro, these agonists significantly induced secretion of cytokines IL-6, IL-1 beta, IL-10, TNFa, IFNa, and IP-10 in human and mouse whole blood. Pharmacokinetic and pharmacodynamic studies in mice showed a significant secretion of IFN alpha and TNF alpha cytokines. When combined with aPD1 in a CT-26 tumor model, the lead compound showed strong synergistic antitumor activity with complete tumor regression in 8/10 mice dosed using the intravenous route. Structure-activity relationship studies enabled by structure-based designs of TLR7 agonists are disclosed.

Utilizing quinoline as a mild, catalytic additive, broadly applicable conditions for the Ni/photoredox-catalyzed C(sp²)-C(sp³) cross-coupling of (hetero)aryl bromides and alkyl pinacolboronate esters were developed, which can be applied to both batch and flow reactions. In addition to primary benzylic nucleophiles, both stabilized and nonstabilized secondary alkyl boronic esters are effective coupling partners. Density functional theory calculations suggest that alkyl radical generation occurs from an alkyl-B(pin)-quinoline complex, which may proceed via an energy transfer process.

Inhibition of TGFβ signaling in concert with a checkpoint blockade has been shown to provide improved and durable antitumor immune response in mouse models. However, on-target adverse cardiovascular effects have limited the clinical use of TGFβ receptor (TGFβR) inhibitors in cancer therapy. To restrict the activity of TGFβR inhibitors to tumor tissues and thereby widen the therapeutic index, a series of tumor-activated prodrugs of a selective small molecule TGFβR1 inhibitor 1 were prepared by appending 1 to a serine protease substrate and a half-life extension fatty acid carbon chain. The prodrugs were shown to be selectively metabolized in tumor tissues relative to the heart and blood and demonstrated a prolonged favorable increase in the tumor-to-heart ratio of the active drug in tissue distribution studies. Once-weekly administration of the most tissue-selective compound 10 provided anti-tumor efficacy comparable to the parent compound and reduced systemic exposure of the active drug.

High-throughput purification workflow in support of microscale (1–5 μmol or 0.5–2 mg) library synthesis.

The multifunctional cytokine TGFβ plays a central role in regulating anti-tumor immunity. It has been postulated that inhi-bition of TGFβ signaling in concert with checkpoint blockade will provide improved and durable immune response against tumors. Herein, we describe a novel series of 4-azaindole TGFβ receptor kinase inhibitors with excellent selectivity for TGFβ receptor 1 kinase. The combination of compound 3f and an anti-mouse-PD-1 antibody demonstrated significantly improved anti-tumor efficacy compared to either treatment alone in a murine tumor model.