Every advance against cancer reveals the same truth: this is a disease that has “learned” to fight back. There are more than 200 types of cancer, and the biology of a tumor is constantly changing. Block one pathway of cell growth and the cancer cells will find another, making resistance a common challenge in cancer treatment. Scientists continue to explore new options to circumvent cancer’s escape tactics. This is no minor feat, and it is exactly what many small molecule cancer medicines are intended to do.
Rather than working on the surface of cells like some cancer medicines, small molecules are able to slip inside the cell to reach targets that larger molecules, such as antibodies, cannot access. From there they shut down the faulty signals that drive tumor cell proliferation. Designing a small molecule is a bit like crafting a key to fit a lock: the structure and chemical properties must align precisely with the target to block cancer progression.
More precise medicines
In the 1940s small molecules were first introduced as chemotherapies that broadly attacked dividing cells throughout the body. Over time, scientists learned how to make these medicines more precise. Newer generations of small molecules target proteins and pathways that are more specific to cancer cells, minimizing the impact on healthy cells and, as a result, making the medicine more tolerable for patients.
One important advance came in breast cancer, where in the 1970s and 1980s early discoveries of key regulators of the cell cycle—cyclins and cyclin-dependent kinases—paved the way for the development of CDK4/6–targeted therapies as a novel class of treatments. These therapies help slow tumor growth by inhibiting CDK4 and CDK6, two key proteins that regulate cell division. As science advanced, the emergence of CDK4/6 inhibitors marked a turning point that proved that these small molecules could be effective breast cancer treatments.
Next-generation small molecules
Pfizer is focused on advancing novel small molecules that can overcome common challenges in cancer, such as treatment resistance and tolerability. One way we’re doing this is to more precisely target known cellular growth pathways. In breast cancer, we are developing new molecules targeting cell cycle dysregulation, such as highly selective CDK4 and CDK2 inhibitors. Because CDK6 is critical for healthy blood cells, a therapy that selectively targets CDK4 or CDK2 with minimal impact to CDK6 may result in fewer treatment side effects. Another way we’re advancing small molecule research is to identify additional important targets within cancer cells that can trigger uncontrolled cell growth. One promising target is the enzyme EZH2, which is highly expressed in prostate cancer cells and helps control whether genes are turned on or off, potentially driving unregulated cell proliferation. By targeting EZH2, the goal is to block one of cancer’s escape routes and open the door for new treatment combinations.
If clinical development and regulatory approvals are successful, the hope is that these next-generation small molecule medicines will work on their own or in combination with other therapies to offer effective treatment options that benefit patients with hard-to-treat cancers.
While not the newest modality in the cancer therapy toolbox, small molecules continue to play a critical role in cancer treatment. Small molecules can effectively reach critical intracellular targets that include many underlying drivers of cancer. The same science that built Pfizer’s leadership in small molecules will continue to guide their impact for years to come. As a central part of our work to help people with cancer live better and longer lives, small molecules represent both our history and our future.
