In This Issue

Discovery of a First-in-Class Inhibitor of the Histone Methyltransferase SETD2 Suitable for Preclinical Studies

Histone methyltransferases (HMTs) have been implicated in a variety of oncology indications due to the changes in gene expression resulting from aberrant methylation events. SET domain-containing protein 2, SETD2, is one of these HMTs and possesses a unique functional profile. To further understand the role of SETD2, compounds with improved in vitro and in vivo properties are required.

In this Issue, Farrow et al. (DOI: 10.1021/acsmedchemlett.1c00272) describe the optimization of an HTS hit to the tool compound EPZ-719 for interrogating the biology of SETD2. Utilizing SETD2 biochemical activity as a readout, an HTS was conducted and two related methylindole scaffolds (IC₅₀ 166 and 52 μM) were confirmed as hits. These compounds were found to be noncompetitive with the substrate (SAM) and were confirmed biophysically through SPR. Enabled by a crystal structure, the team was able to identify several more starting points which led to a focused effort on a series of amide analogues. Ensuing characterization demonstrated additional modifications to the core were required and subsequent efforts yielded the diamine series that eventually yielded EPZ-719 with desired pharmacokinetic profile for interrogation of SETD2 in vivo.

Synthesis and Preclinical Evaluation of [68Ga]SP94 for Micro-PET Imaging of GRP78 Expression in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a disease where improved incidences of early diagnoses could provide a significant impact to patient survival, as the effective treatment options are limited in the advanced stages where it is typically diagnosed. One way to increase diagnoses is through using positron-emission tomography (PET) to visualize the tumor and its environment. GRP78 is a protein that is overexpressed in a variety of oncology indications and can promote not only survival and proliferation to tumors but also metastasis and resistance to chemotherapies.

In this Issue, the combined teams of Jiang and Sun (DOI: 10.1021/acsmedchemlett.1c00350) report a synthesis of a new radiotracer for monitoring GRP78 expression. Following up on their previous discovery that GRP78 was a membrane receptor of a short peptide, SP94, the team embarked on an effort to synthesize PET tracers using this peptide and the radionuclide ⁶⁸Ga. Following the synthesis of this radiotracer, [⁶⁸Ga]SP94 was evaluated in a variety of different settings and strikingly showed rapid and higher uptake in HepG2 tumors and was associated with the level of GRP78 expression.

Discovery of Dolastatinol: A Synthetic Analog of Dolastatin 10 and Low Nanomolar Inhibitor of Tubulin Polymerization

Natural products can provide potent starting points for physiological intervention. One of these starting points is dolastatin 10, a cytotoxic pentapeptide. This peptide exhibits subnanomolar cytotoxicity resulting in its dramatic influence on tubulin biology. Dolostatin 10 has even been investigated in clinical trials but failed due to significant off-target cytotoxicity. However, due to the high cytotoxicity of this class of peptides, dolostatin 10 has provided a starting point for several related clinical warheads for antibody–drug conjugates.

In this Issue, Gellerman et al. (DOI: 10.1021/acsmedchemlett.1c00432) have synthesized a methylene hydroxyl derivative of dolastatin 10 resulting in a highly potent anticancer agent. Enabled by solid-phase peptide synthesis with a key introduction of a self-immolative linker, the team was able to synthesize dolastatinol. This linker was critical to achieve an increase in the overall yield of the product. The resulting modified dolastatin maintained its activity, including in mitotic arrest, and proved highly potent in both HER2-positive and triple negative breast cancer cell lines. Moreover, the dolastatinol compound now provides a linker position for future conjugations.