About Small Molecules
Targeted inhibition of intracellular tumor mechanisms
Over the last decade, we have pioneered foundational research behind targeted antitumor strategies with small molecules—a cornerstone of modern precision medicine. Through continued exploration of diverse tumor targets, we strive to further advance the potentially complementary role of small molecules in combined regimens for patients who have limited treatment options.
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
We are exploring ways to selectively target vulnerabilities in cancer cells using small molecules
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. 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
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. Inhibition of MDM2-TP53 interaction aims to stabilize TP53 and may offer a novel antitumor strategy.9-14
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
We are investigating the potential of small molecules as single agents and in combination with PD-L1 inhibition, as well as with chemotherapy and antihormonal therapies.
- Gerber DE. Targeted therapies: a new generation of cancer treatments. Am Fam Physician. 2008;77:311-319.
- Wang M, Yu Y, Liang C, Lu A, Zhang G. Recent advances in developing small molecules targeting nucleic acid. Int J Mol Sci. 2016. doi:10.3390/ijms17060779.
- Lin J, Sampath D, Nannini MA, et al. Clin Cancer Res. 2013;19:1760-1772.
- Hung C-M, Garcia-Haro L, Sparks CA, Guertin DA. mTOR-dependent cell survival mechanisms. Cold Spring Harb Perspect Biol. 2014. doi:10.1101/cshperspect.a008771.
- Gabelli SB, Mandelker D, Schmidt-Kittler O, Vogelstein B, Amzel LM. Somatic mutations in PI3Kα: structural basis for enzyme activation and drug design. Biochim Biophys Acta. 2010;1804:533-540.
- Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017;169:381-405.
- Cheng JQ, Lindsley CW, Cheng GZ, Yang H, Nicosia SV. The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene. 2005;24:7482-7492.
- Malanga D, Scrima M, De Marco C, et al. Activating E17K mutation in the gene encoding the protein kinase AKT in a subset of squamous cell carcinoma of the lung. Cell Cycle. 2008;7:665-669.
- Ding Q, Zhang Z, Liu J-J, et al. J Med Chem. 2013;56:5979-5983.
- Oren M. Decision making by p53: life, death and cancer. Cell Death Differ. 2003;10:431-442.
- Vassilev LT. MDM2 inhibitors for cancer therapy. Trends Mol Med. 2007;13:23-31.
- Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res. 1998;26:3453-3459.
- Tan BX, Khoo KH, Lim TM, Lane DP. Oncotarget. 2013;5:933-943.
- Vu BT, Vassilev LT. Curr Top Microbiol Immunol. 2011;348:151-172.
- Knight T, Irving JAE. Ras/Raf/MEK/ERK pathway activation in childhood acute lymphoblastic leukemia and its therapeutic targeting. Front Oncol. 2014;4:160.
- Tran KA, Cheng MY, Mitra A, et al. MEK inhibitors and their potential in the treatment of advanced melanoma: the advantages of combination therapy. Drug Des Devel Ther. 2015;10:43-52.