Explore Small Molecules

Targeted inhibition of intracellular tumor mechanisms

Over the last decade, Genentech has pioneered foundational research behind targeted antitumor strategies with small molecules—a cornerstone of modern precision medicine. Through continued exploration of diverse tumor targets, Genentech strives to further advance the potentially complementary role of small molecules in combined regimens for patients who are currently underserved.

Small molecules are low-weight, chemical-based compounds and are referred to by their size in contrast to larger, biological molecules, such as monoclonal antibodies and other proteins. Unlike monoclonal antibodies, which primarily target extracellular tumor components, such as ligands and receptors, small molecules are able to pass through cellular membranes to engage intracellular targets.1

Inside the tumor cell, small molecules bind to proteins or nucleic acids and are designed to regulate the activity of the target by inhibiting its function or by disrupting specific protein-protein interactions.1,2

Genentech is exploring selective targeting with small molecules to exploit vulnerabilities in cancer cells

Small-molecule inhibition of AKT aims to antagonize the effect of PTEN-loss

AKT, a key component of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, is dysregulated in many malignancies, often through the acquisition of activating mutations in AKT and PI3K, loss of the tumor suppressor phosphatase and tensin homolog (PTEN), or amplification of AKT and PI3K. Small-molecule inhibition of AKT aims to antagonize the effect of PTEN-loss, aberrant AKT signaling, and mutation of phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA), the most commonly mutated oncogene.3-8

Small molecule inhibition of MDM2 aims to block MDM2 interaction with p53

The tumor suppressor protein 53 (TP53) is a powerful growth suppressive and pro-apoptotic protein that plays a central role in protection from tumor development and is frequently inactivated in human cancers. Some tumors overproduce the negative TP53 regulator murine double minute 2 (MDM2), which can disrupt or disable the tumor-suppressive function of TP53. MDM2 binds TP53 and negatively modulates its transcriptional activity and stability. Small-molecule inhibition of MDM2-TP53 interaction aims to stabilize TP53 and may offer a novel antitumor strategy.9-14

Small-molecule inhibition of MEK aims to disrupt the MAPK signaling cascade

Abnormal activation of the mitogen-activated protein kinase (MAPK) pathway plays a role in some cancers. The activation of MEK, a protein kinase in the MAPK pathway, can lead to cell survival and proliferation. Small-molecule inhibition of MEK aims to disrupt the MAPK signaling cascade, potentially resulting in tumor cell death.15,16

Genentech is investigating the potential of small molecules as single agents and in combination with PD-L1 inhibition, as well as with chemotherapy and antihormonal therapies.


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