The blockbuster drug Palbociclib found the beginning and end

Big Bomb drug Palbociclib found the beginning and end

Palbociclib (Figure 1) is a highly selective, reversible cyclin-dependent kinase (CDK) inhibitor developed by Pfizer. Inhibition by CDK4/6 can result in inhibition of cell cycle progression from G1 to S phase, blocking DNA synthesis and thus for treating menopausal women with metastatic breast cancer. The drug was approved by the FDA for breast cancer treatment in 2015 and became a blockbuster product in the first year of marketing. In 2015, it sold $723 million and 2016 sales of $2.135 billion.

Big Bomb drug Palbociclib found the beginning and end

As the first listed drug for CDK4/6 inhibitors, it is necessary to sort out the development process and provide reference and reference for the development of innovative drugs in China.


CDK kinase is a class of proteins involved in cell cycle regulation that phosphorylate target proteins and regulate cell cycle progression. The CDK kinase family includes CDK1-13 members, and different members of the CDK family play different roles in cell cycle regulation. Among them, CDK4/6 is highly homologous and plays a decisive role in the process from G1 to S phase. CDK4/6 binds to Cycling D to phosphorylate downstream Rb protein, which determines whether cells are transferred from G1 to S phase. Thereby preventing the cell cycle progression (Fig. 2), it acts to inhibit cell proliferation and kill tumors.

Big Bomb drug Palbociclib found the beginning and end

Figure 2 CDK4/6 plays a role in cell cycle transition (Source: Expert Opin. Pharmacother. 2014, 15(3): 407-420)

Palbociclib Discovery History

The development of CDK inhibitors has gone through three phases:

The first generation of non-specific CDK inhibitors, Includes Flavopiridol, UCN-01 and Butyrolactone (Figure 3). This kind of compound did not have an in-depth understanding of its mechanism of action during clinical research, but it was presumed to be a CDK inhibitor during the course of patient administration. Due to lack of specificity, these compounds did not go to market. The structure of such CDK inhibitor compounds is not of the same type and lacks regularity.

Big Bomb drug Palbociclib found the beginning and end

Figure 3 First and second generation CDK inhibitors

The second generation is a selective CDK1/2 inhibitor with structural features A scorpion mother nucleus. Representative compounds are Olomoucine, Seliciclib and Purvalanol derivatives (Fig. 3), of which Seliciclib is currently undergoing Phase II clinical studies of non-small cell lung cancer.

The third generation of specific CDK inhibitors, the focus of this phase of research is mainly CDK1/2 inhibitors, but more compounds began to focus on CDK4 inhibitory activity. Among them, the pyrido[2,3-d]pyrimidin-7-one compound (Fig. 4) jointly discovered by Warner Lambert (acquired by Pfizer in 2000) and Onyx Pharmaceutical Company is such a typical representative, and was later developed by Pfizer Palbociclib. Foundation.

Big Bomb drug Palbociclib found the beginning and end

Fig. 4 Third-generation CDK inhibitors

pyrido[2,3-d]pyrimidin-7-one compounds Optimized, PD0183812 was obtained, which has better CDK4/6 activity, but CDK subtype selectivity needs to be improved. Studies on the substituted amino group at the C2 position of the parent ring revealed that the 2-aminopyridyl compound 15a has a CDK4 inhibition selectivity superior to that of the anilino group 15b (Fig. 5). More directly, it can be seen that 2-aminopyridyl compound 17 is superior to anilino 16 in CDK4 selectivity.

Big Bomb drug Palbociclib found the beginning and end

Figure 5 C2 substitution optimization (Source: J. Med. Chem. 2005, 48, 2388-2406)

Further research findings When the C5, C6 and C2 side chain substitutions in the pyridyl[2,3-d]pyrimidin-7-one parent ring are changed, the methyl group is introduced at the C5 position and the acetyl group is introduced at the C6 position, and the selectivity of CDK4 is greatly improved (Fig. 6). .

Big Bomb drug Palbociclib found the beginning and end

Figure 6 C5, C6 and C2 side chains affect selectivity (Source: J. Med. Chem. 2005, 48, 2388-2406)

Continue to investigate the effect of C6 substitution and C2 side chain substitution on activity: C6 acetyl is optimal, C2 side chain is substituted with piperazine (43), homopiperazine (57), 4-hydroxypiperidine (59) Both CDK4 selectivity and in vitro cell viability achieved good results when combined with morpholine (60) (Fig. 7).

Big Bomb drug Palbociclib found the beginning and end

Figure 7 C6 position, C2 side chain substitution optimization (Source: J. Med. Chem. 2005, 48, 2388-2406)

In-depth evaluation found that Compound 43 is the optimal candidate, which has drug-forming characteristics in terms of CDK4/6 inhibitory activity, pharmacological properties, and other pharmaceutical properties. Compound 43 was developed for the subsequent development of the marketed drug Palbociclib.


New drug development is a complex process involving multidisciplinary assessments. The efficacy, pharmacokinetics, and safety determine the success or failure of a drug.


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