Morphic Therapeutics Submits Prospectus Highlighting MORF-057, an Oral α4β7 Integrin Inhibitor Developed with Schrödinger’s Computational Platform

Morphic Therapeutics was recently acquired by Eli Lilly for $3.2 billion. Its core asset is MORF-057, an integrin inhibitor currently in Phase II clinical trials. Due to the company's deep collaboration with Schrödinger, a computational drug software/discovery company, it was previously mentioned in Schrödinger’s materials, providing a good opportunity to briefly share some insights.

Project Background: See the following figures together.

First, the target α4β7 is a validated target, and there have been antibody drugs on the market before. (2014), but(For this target)Small molecule drug development is relatively challenging.

Secondly, Morphic's molecular discovery did not start from scratch but stood on the shoulders of giants. Hits/leads with decent activity had already been reported, and even co-crystal structures had been disclosed.

But even so, the discovery of small molecules for this target remains quite challenging, with further improvements needed in activity, selectivity, and oral absorption.(The small molecule contains a virtually irreplaceable carboxyl group)`, no one has achieved it before.`。

To date, there have been no reports on the optimization process of the molecule, and the structure of the clinical molecule has not been disclosed.(From the perspective of the representative molecules in the patent, the carboxyl group is still retained and may contain a basic nitrogen.)。

But since there is a deep cooperation with Schrödinger, Schrödinger also considers it a successful case of collaboration.(Other includes Nimbus and the earlier Agios. Nimbus goes without saying. Agios launched two FIC IDH inhibitors, in which Schrödinger also participated, but it was a long time ago, with limited information disclosed, so the importance of its role is uncertain.)One of, which naturally involves computational participation.

According to the disclosed information, the main application of FEP is to relatively accurately predict activity and to assist in predicting parameters related to oral absorption by quantitatively calculating pKa, etc. Additionally, LiveDesign was mentioned, which is a cloud-based collaboration platform that integrates experimental and computational results for data sharing.

The figure below shows an overview and results of the molecular optimization process. The horizontal axis represents activity, the vertical axis represents membrane permeability, and the dark blue dots indicate earlier molecules. (Including the reported molecules), the light blue dots are the molecules they made later.

Among them, the black star AJM, also known as AJM300, was actually a drug approved in Japan in 2022. (Currently, it should also only be approved in Japan), but it can be seen that its activity and membrane permeability are relatively poor. In fact, it requires three times daily dosing and has significant off-target effects.α4β1NoSelectivity.

The orange star and green star are two early milestone molecules of Morphic, mainly in the improvement of activity.(Green Star molecules are 200 times stronger than AJM), The potential candidates within the black frame have been further optimized to maintain high activity while improving membrane permeability. The significance of the three yellow stars is unclear, but one of them might be the clinical molecule MORF-057.。

Finally,Comparison of MORF-057 with Competitors, Two of Which Are Antibodies(Including the marketed Vedolizumab)，MORF-057 is taking the small-molecule oral route, showing relatively clear differentiation. A more direct comparison would be with the small molecule AJM300, where activity has increased nearly 80-fold.(Compared to an already marketed drug), while improving selectivity and oral absorption.

Although there is no specific structure(AJM300 structure can be found), but the two should be the same binding pocket, the same binding mode optimized respectively, able to outperform an approved drug(Although approved only in Japan)It is not easy to achieve such obvious improvements. The extent to which calculations play a role is still open to interpretation. As the saying goes, "Only when you meet it do you realize its presence, like a rainbow."Only those involved understand.