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Molecules in Motion: An Oral G12D Inhibitor and Allosteric Cbl-b Inhibitor Entering Development

Our latest roundup of small molecules in the news includes three molecules moving into development for the first time:

MRTX1133

Mirati’s reversible, long-acting KRASG12D inhibitor, and December ‘21 Molecule of the Month, is going into the clinic as an oral compound. While initial disclosures referred to its potential as an IV agent, Mirati recently announced IND clearance for a Ph. I study with MRTX1133 given orally.

HST-1011

Hotspot Therapeutics, a company focused on oral, allosteric small molecules, received IND clearance for HST-1011, an allosteric inhibitor of E3 ligase Cbl-b. HST-1011 is stated to have low nM potency, a slow dissociation rate, and Cbl-b vs. c-Cbl selectivity, and is Hotspot’s most advanced program. While HST-1011 has not been disclosed and the discovery is stated by the company to have been enabled by Hotspot’s “Smart Allostery” platform, recently patented Cbl-b inhibitors from Hotspot Therapeutics appear to be related to Nurix’s original allosteric Cbl-b inhibitors.

bexotegrast (PLN-74809)

Pliant’s oral, dual-selective αvβ6 and αvβ1 integrin inhibitor was recently reported to demonstrate dose-dependent improvement in lung function (40-320 mg QD) and was well tolerated at the highest dose of 320 mg in a Ph. IIa safety/exploratory efficacy trial in idiopathic pulmonary fibrosis (IPF). Inhibition of αvβ6 and αvβ1 integrin  acts upstream of TGF-β, ultimately inhibiting its signaling without the well-known side effects of systemic TGF-β inhibition. This is significant given the difficulty in treating IPF, the longstanding challenge in identifying integrin inhibitors and effective TGF-β modulators, along with the recently reported preclinical non-human primate toxicology findings with Morphic Therapeutics’ αvβ6 inhibitor MORF-627.

In our full update of small molecules in the news we also cover recent:

  • (B)Million Dollar Molecules: recent mergers and acquisitions
  • Molecules in Motion: clinical trial updates and FDA filings
  • Molecules of the Month – Where Are They Now?: updates on past Drug Hunter MotM
  • Potential upcoming approvals: recent NDA filings and upcoming PDUFA dates

Read about all 14 molecules in the full Premium article here:

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