Future of small-molecule drugs lies in oral formulations

By Samantha Black, PhD, ScienceBoard editor in chief

July 12, 2021 -- The way forward for small-molecule drug manufacturers is through orally administered products, according to Spiro Rombotis, president and CEO of Cyclacel, who recently spoke with ScienceBoard.net.

While biologics have been touted as the future of medicine, Rombotis noted that immuno-oncology drugs or immuno-oncology combination therapies serve only around one in five cancer patients. Moreover, the field is still an emerging area of research that is in flux and rapidly evolving.

For the other four out of five patients, cell therapy approaches such as CAR T or allogeneic stem cell transplantation hold promise. But the industry is still grappling with exorbitant price tags and side effects like cytokine release syndrome.

Spiro Rombotis, president and CEO of Cyclacel.
Spiro Rombotis, president and CEO of Cyclacel.

This leaves a large unmet gap in treatment options, where small-molecule therapies can play a role, Rombotis explained.

But the small-molecule industry can do better than the traditional chemotherapy look-alike drugs that immediately come to mind. He said that the industry is moving toward drugs that are well tolerated, given by mouth without toxicity, can be administered in the comfort of a patient's home, and taken for life. The vision that Rombotis details is one where cancer is managed like a chronic disease like diabetes and insulin injections.

Cyclacel is a developer of small-molecule therapeutics that was founded by leading cell cycle biologist Sir David Lane, PhD, in 1997. The company has several small-molecule drug candidates that fill the unmet needs of cancer patients.

Targeting cancer drug resistance

Some of Cyclacel's foundational work involved experiments that determined that the combination of cyclin-dependent kinase 2 (CDK 2) and CDK 9 inhibitors is more powerful in blocking the cell cycle than independent administration of either molecule. After making this discovery, the company synthesized a series of over 400 compounds that targeted both CDK 2 and CDK 9. The company selected to advance fadraciclib (fadra), among the large number of analogs, Rombotis explained.

Cyclacel utilized in-house structure-based drug design approaches to determine the 3D structure of the molecule and conducted molecular docking simulations to determine the optimal binding location.

The idea behind fadraciclib is to tackle chemotherapy drug resistance. Resistance occurs when traditional cancer therapies fail to kill all of a patient's cancer cells. The few resistant cells that survive hide in parts of the bone marrow, where it is very hard to reach them with conventional therapies. Eventually, these cells can cause a relapse via acquired genetic resistance. During this process, cancer cells evolve and express new proteins that are not targeted by the initial therapy.

Fadra can be administered as a second- or third-line therapy to target resistance proteins, suppress them, and delay or prevent relapse. The drug can induce the body's own process of programmed cell death (apoptosis) by targeting CDK 2 and CDK 9, which will lead to cancer cells committing suicide and allow regular cells to return to normal cell cycle functions.

Cyclacel has invested significant resources into the development of fadra as both an intravenous (IV) and oral drug. The process of developing an oral formulation is not straightforward and relies on an intimate understanding of the structure-activity relationship of the molecule to make the molecule more soluble without loss of efficacy.

This requires extra manufacturing steps, according to Rombotis, but is still relatively less complex than biologics manufacturing and is still economically viable because of economies of scale, which are difficult to achieve with biologics.

This is not a new concept, as traditional chemotherapy treatments are laborious and have severe side effects. But Rombotis explained that the industry now has far more sophisticated tools (i.e., genetic profiling to identify elevated proteins) to guide the development and treatment of targeted small-molecule therapies.

These precision medicine approaches use next-generation sequencing and liquid biopsy to identify tumor cells and actionable protein targets from noninvasive patient samples. Simple searches in advanced databases will help practitioners draw useful associations and correlations about the patient's information to guide their treatment selection.

Catching cancer at the last step

Concurrent with the development of its fadra program, Cyclacel is also developing a second small-molecule candidate, called CYC140, a pololike kinase 1 (PLK-1) inhibitor, that targets the last stage of the cell cycle, mitosis. This molecule was discovered by David Glover, PhD, Cyclacel's chief scientific officer, who joined the company shortly after its founding, Rombotis explained.

This approach intervenes with cancer cell division at the last possible opportunity. By blocking cancer cell mitosis, CYC140 prevents cancer cells from passing DNA mistakes to daughter cells. Importantly, this molecule works to jam cell division in only cancer cells. Glover's work demonstrated that PLK-1 in normal cells are not susceptible to PLK-1 inhibition, while cancer cells are very vulnerable once the PLK-1 signal is depleted.

Because cancer cells are dependent on PLK-1 (but not normal cells), CYC140 is highly selective and preclinical work points to very high activity toward PLK-1. The company has demonstrated that the drug targets PLK-2 and PLK-3 to a lesser degree than PLK-1 but doesn't interact with other molecules in the same family with very similar structures.

Based on this information, Cyclacel is developing the candidate in both IV and oral formulations. However, Rombotis noted that only the oral formulation is being evaluated in upcoming clinical trials, emphasizing the company's focus on a new era of oral small-molecule cancer therapies.

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