MPC-3100

Biological Activity

MPC-3100 is a fully synthetic potent small-molecule Hsp90 inhibitor with an IC50 of 60 nM. MPC-3100 time-dependently decreases client protein levels with maximal reduction by 24 hours in HCT-116, NCI-N87 and DU-145 cells. The IC50 values for client protein reduction ranges from 0.1 mM to 0.5 mM, comparable to the cellular cytotoxicity values of MPC-3100 at 72 hours for the various cell lines. Following intravenous administration of MPC-3100 to rats, fourteen metabolites are observed in the feces; whereas, only 6 metabolites are observed in urine. No glucuronides are found in either the urine or feces. Less than 1% of the dose is recovered in rat urine; whereas, up to 40% of the dose is recovered as MPC-3100 and metabolites in feces over a 24 hour period. As many as 25 different metabolites are observed in the bile based upon differences in their retention time and molecular weight. Most of the metabolites in the bile resulted from either glucuronidation or sulfation, some of which are conclusively identified with authentic standards.MPC-3100 at the dose of 200 mg/kg is effective when dosed either daily (40% regression), once every other day (7% regression), twice weekly (89% TGI) or at 400 mg/kg twice weekly (87% TGI) for three weeks.Although the 200 mg/kg daily schedule is significantly more effective than all other schedules at the end of dosing on Day 21, there is no significant difference in TGI (79 to 87%) between the various schedules at the end of the study on Day 39. The anti-tumor activity of MPC-3100 is compared with erlotinib in a lung cancer (A549) xenograft model sensitive to EGFR prevention. MPC-3100 dosed daily for 21 days at 150 or 200 mg/kg prevents tumor growth by 88% or leads to the regression of tumor by 16%, respectively, and is more effective than erlotinib at its maximum tolerated dose of 100 mg/kg daily (88% TGI). MPC-3100 is also active in a pancreatic cancer (MIA PaCa-2) xenograft, exhibiting 67% and 95% TGI when dosed daily at 150 mg/kg or 200 mg/kg for 15 days. Tumor growth prevention observes with MPC-3100 in MIA PaCa-2 compared favorably to that observed with 5-fluorouracil. Oral MPC-3100 appears to be safe and tolerable even up to 600 mg? per? day. Side-effects were manageable and reversible upon? discontinuation of MPC-3100. MPC-3100 has been completed in phase I clinical trials for the treatment of cancer.

Chemical Information

Molecular Weight	549.44
Formula	C22H25BrN6O4S
CAS Number	958025-66-6
Solubility (25°C)	DMSO
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Asma Nazar, et al. Deciphering the Inhibition Mechanism of under Trial Hsp90 Inhibitors and Their Analogues: A Comparative Molecular Dynamics Simulation

[2] Se-Ho Kim, et al. Discovery of an L-alanine ester prodrug of the Hsp90 inhibitor, MPC-3100

[3] Katerina Sidera, et al. HSP90 inhibitors: current development and potential in cancer therapy

[4] Se-Ho Kim, et al. Discovery of (2S)-1-[4-(2-{6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9H-purin-9-yl}ethyl)piperidin-1-yl]-2-hydroxypropan-1-one (MPC-3100), a purine-based Hsp90 inhibitor