Hengrui Medicine's 1.3 billion innovative drug Punaburin will be another wealth code?

PART01.

PART01.

On August 26, 2021, Hengrui Medicine's blockbuster transaction of 1.

Significantly improved the survival benefits of patients, and observed a long-tailing effect survival curve, significantly reduced the incidence of grade 4 neutropenia (CIN), and improved the quality of life.

CIN (chemotherapy-induced neutropenia)

The main adverse reactions caused by patients with neutropenia after receiving G-CSF standard treatment are:

1) Bone pain: about 10% to 30% of patients have mild to moderate bone pain

2) Allergic reactions, including allergic reactions of the skin, respiratory system or cardiovascular system

3) Rupture of the spleen: There are reports of cases of rupture of the spleen after the use of G-CSF, some of which are fatal

4) Pulmonary toxicity: It is seen in patients with Hodgkin’s lymphoma who receive chemotherapy with bleomycin-containing regimens, especially after ABVD regimen (bleomycin given once every 2 weeks), G-CSF treatment can cause pulmonary toxicity

5) Other potential toxicity: including acute respiratory distress syndrome, alveolar hemorrhage, sickle cell disease and other sickle cell crisis occurs

At present, there are a large number of unmet clinical needs for CIN to be solved urgently

The above series of amazing results make people can't help but curious about punabrin, the FIC drug, and the author discusses how it was discovered and modified

PART02.

PART02.

The study of phenylahistin found that phenylahistin showed strong cytotoxicity to a variety of tumor cells

In July 2004, the US NEREUS Pharmaceutical Company disclosed the chemical modification of phenylahistin for the first time in the patent WO2004054498 (A2), and discovered punabrin (KPU-2.

In July 2004, the US NEREUS Pharmaceutical Company disclosed the chemical modification of phenylahistin for the first time in the patent WO2004054498 (A2), and discovered punabrine (KPU-2.

The idea of ​​modification in patent WO2004054498 (A2) is mainly to eliminate the chirality to obtain dehydrophenylazistin, connect different substituent fragments to the left benzene ring, and modify the fragments on imidazole to finally obtain Punabrin

Figure 1 The transformation of Puna Brin

In the 2006 Anti-Cancer Drugs article, NPI-2358 (KPU-2) was tested on six different human tumor cell lines.
These cell lines represent multiple tumor types.
NPI-2358 has an IC50 value of 9.
8 ~ 18 nmol/L
.
In addition, NPI-2358 has almost the same cytotoxic activity on MDR tumor cells (MES-SA/Dx5) overexpressing P-gp (MES-SA/Dx5) or tumor cells with altered Topo II activity (HL-60/MX2) (respectively only reduced 1.
1 times and 1.
9 times), while Paclitaxel (paclitaxel) and Mitoxantrone (mitoxantrone) encountered mutant cell lines inhibitory activity decreased by 1143 times and 16 times, respectively
.
These pre-clinical data also reflect the clinical advantages of punabrin for drug-resistant cell lines
.

These pre-clinical data also reflect the clinical advantages of punabrin for drug-resistant cell lines
.

Figure 2 The inhibitory activity of punabulin on tumor cell lines and drug-resistant tumor cell lines

In 2011, Professor Hayashi summarized the structure-activity relationship of punabrine modified by phenylahistin (see Figure 3): 1.
L-type phenylalanine residues are required; 2.
DKP and The rigid planar pseudo-tricyclic structure formed by the hydrogen bonds between the imidazole rings; 3.
The 5-position of the imidazole ring needs to be connected to a quaternary carbon atom, and the vinyl group is not necessary
.

The structure-activity relationship of punabrine is obtained by modification (see Figure 3): 1.
L-type phenylalanine residue is required; 2.
The rigid planar pseudo-tricyclic structure formed by the hydrogen bond between DKP and the imidazole ring; 3.
The 5-position of the imidazole ring needs to be connected to a quaternary carbon atom, and the vinyl group is not necessary
.

Figure 3 Structural entities required for effective biological activity of compounds

Due to the low solubility of punabrine, it is necessary to be injected with a solubilizer in clinical practice.
The modification of punabrine also focuses on improving the solubility.
For example, the left benzene ring of punabrine is changed to aryl ketone, C The ring was changed to pyridine to obtain KPU300.
Its inhibitory activity on Hela and A549 was better than punabrine, but the solubility was not improved
.

Due to the low solubility of Panabrin, it is clinically necessary to combine injection with a solubilizer.
The transformation of Panabrin also focuses on improving the solubility.

In order to improve the water solubility of punabulin, Hayashi et al.
designed and synthesized a series of punabulin prodrugs .
The solubility of compound (2) is 64000 times higher than that of punabulin.
It can be hydrolyzed to release punabulin under the action of esterase.
Brin
.

Punabrine prodrug

Prodrugs account for about 5% of all drugs.
Because the activation of prodrugs requires the participation of enzymes, the enzymes that activate prodrugs may have genetic polymorphisms, which will cause differences between different subjects.
In addition, drug-drug interactions may also occur
.
Generally, prodrug strategies are considered only when the existing pharmacophore cannot obtain the required pharmacological and pharmacokinetic properties
.

Generally, prodrug strategies are considered only when the existing pharmacophore cannot obtain the required pharmacological and pharmacokinetic properties
.

Figure 4 KPU-300 found in the modification of A ring and C ring

Figure 5 Prodrug of punabrin

Since the original patent does not protect the deuterated compounds, Qingdao Marine Biomedical Research Institute has conducted in-depth research on the deuterated compounds of punabulin, and the patent has been authorized.
The candidate compound MBRI-001 is currently in the preclinical research stage
.
Deuterated drugs have been controversial in recent years, and the production cost of deuterated drugs is usually several times higher
.

In the 2018 BMC (https://doi.
org/10.
1016/j.
bmc.
2018.
08.
009), Figure 6 shows that MBRI-001 is stable in rat plasma and more stable in liver microsomes than plinabulin, in the text The other data listed also show that in the body, MBRI-001 can be rapidly and widely distributed in various tissues, especially MBRI-001 is significantly higher than other tissues in lung tissue
.
Excretion studies indicate that MBRI-001 may be broken down and excreted as a metabolite
.
In addition, the combination of MBRI-001 and gefitinib has a better anti-tumor inhibition rate in vivo than a single agent
.

Figure 6 The structure of deuterated punabulin and the stability test of plasma and liver microsomes

Subsequent modifications to punabrine analogues are mainly centered on: 1.
Obtaining more efficient and low-toxic candidate compounds; 2.
Increasing the solubility of the compound, clinically combined with solubilizer injection, long-term use may produce unexpected safety Problems may affect the patient’s quality of life
.

Subsequent modifications to punabrine analogues are mainly centered on: 1.
Obtaining more efficient and low-toxic candidate compounds; 2.
Increasing the solubility of the compound, clinically combined with solubilizer injection, long-term use may produce unexpected safety Problems may affect the patient’s quality of life
.

Dalian Wanchun is a new drug research and development company located in Dalian, Liaoning, and owns the Chinese rights to Plinabulin, a category 1.
1 innovative drug
.
Pranabrin is expected to become the first breakthrough treatment drug in the treatment standard and clinical benefit of severe CIN indications in 30 years
.
At the same time, Wanchun Pharmaceutical will also work with Hengrui Pharmaceuticals to explore the therapeutic potential of punabulin in solid tumors, and match with Hengrui’s existing tumor pipeline.
It is hoped that this new drug will be approved as soon as possible and benefit more tumors.
Patient
.

Pranabrin is expected to become the first breakthrough treatment drug in the treatment standard and clinical benefit of severe CIN indications in 30 years
.

references:

references:

(1) Saskia TC Neuteboom et al.
NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence

(1) Saskia TC Neuteboom et al.
NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence

for activity as a tumor vascular-disrupting agent;Anti-Cancer Drugs 2006.
17:25–31.

for activity as a tumor vascular-disrupting agent;Anti-Cancer Drugs 2006.
17:25–31.

(2) Li Wenbao, et al.
, Research Progress of Marine Antitumor Drug Candidate Pranabrin and its analogues, China Marine Medicine, Vol.
35, Issue 4, 2016.

(2) Li Wenbao, et al.
, Research Progress of Marine Antitumor Drug Candidate Pranabrin and its analogues, China Marine Medicine, Vol.
35, Issue 4, 2016.

(3) Wenbao Li et al.
Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-

(3) Wenbao Li et al.
Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-

001.
a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Bioorganic & Medicinal Chemistry 27 (2019) 1836–1844.

001.
a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Bioorganic & Medicinal Chemistry 27 (2019) 1836–1844.

(4) Wanchunbulin official WeChat: heavyweight: to break the 30-year silence in the CIN field, the Punabulin international multi-center phase III clinical trial PROTECTIVE-2 reached the primary and all key secondary endpoints.

(4) Wanchunbulin official WeChat: heavyweight: to break the 30-year silence in the CIN field, the Punabulin international multi-center phase III clinical trial PROTECTIVE-2 reached the primary and all key secondary endpoints.

(5) Yuichi Hashimoto et al.
Improvement in Aqueous Solubility in Small Molecule Drug Discovery

(5) Yuichi Hashimoto et al.
Improvement in Aqueous Solubility in Small Molecule Drug Discovery

Programs by Disruption of Molecular Planarity and Symmetry.
J.
Med.
Chem.
2011.
54.
1539–1554.

Programs by Disruption of Molecular Planarity and Symmetry.
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Med.
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2011.
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1539–1554.

(6)Yoshio Hayashi; et al.
Synthesis and Structure−Activity Relationship Study of Antimicrotubule Agents Phenylahistin Derivatives with a Didehydropiperazine-2.
5-dione Structure.
J.
Med.
Chem.
2012.
55.
1056−1071.

(6)Yoshio Hayashi; et al.
Synthesis and Structure−Activity Relationship Study of Antimicrotubule Agents Phenylahistin Derivatives with a Didehydropiperazine-2.
5-dione Structure.
J.
Med.
Chem.
2012.
55.
1056−1071.